Abstract
Mitotic cells face the challenging task of ensuring accurate and equal segregation of their duplicated, condensed chromosomes between the nascent daughter cells. Errors in the process result in chromosome missegregation, a significant consequence of which is the emergence of aneuploidy—characterized by an imbalance in chromosome number—and the associated phenomenon of chromosome instability (CIN). Aneuploidy and CIN are common features of cancer, which leverages them to promote genome heterogeneity and plasticity, thereby facilitating rapid tumor evolution. Recent research has provided insights into how mitotic errors shape cancer genomes by inducing both numerical and structural chromosomal changes that drive tumor initiation and progression. In this review, we survey recent findings regarding the mitotic causes and consequences of aneuploidy. We discuss new findings into the types of chromosome segregation errors that lead to aneuploidy and novel pathways that protect genome integrity during mitosis. Finally, we describe new developments in our understanding of the immediate consequences of chromosome mis-segregation on the genome stability of daughter cells.
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Introduction
Aneuploidy is an abnormal state in which the number of chromosomes in a cell or organism deviates from a multiple of the haploid number [1]. First observed over 100 years ago by the German zoologist Theodor Boveri while studying sea urchin embryo divisions [2], it has fascinated generations of scientists since, not least of all because of its association with cancer. Current studies estimate that aneuploidy is pervasive in solid tumors [3], including approximately 30% of prostate tumors [4], 60% of non-small cell lung cancers [5], 70% of colorectal tumors [6], and 60–80% of breast tumors [7]. The degree and spectrum of aneuploidy varies among cancer types—many display recurrent specific chromosomal abnormalities, while others harbor more complex combinations and permutations with no clear specificity [8,9,10,11]. Massive gains and losses of chromosomes, which are primarily caused by chromosome segregation errors during cell division, tend to be deleterious to the cell; therefore, they are limited in human cancer cell lines and tumors [12, 13]. Segmental or structural aneuploidy, in which chromosomal segments are rearranged and often amplified or deleted can also occur, and are often caused by faulty DNA replication or repair [14]. A distinct form of structural aneuploidy called chromothripsis has been more recently recognized as a downstream consequence of mis-segregated chromosomes that become isolated in extranuclear structures known as micronuclei. Chromothripsis is characterized by extensive genomic rearrangements and an oscillating pattern of DNA copy numbers, often restricted to one or a few chromosomes [15]. Whole and segmental chromosomal alterations are not mutually exclusive, and cancer cells can display both, resulting in composite aneuploidy [16]. Distinguishing between whole chromosome and segmental aneuploidy is essential to identifying and understanding their origins.
Aneuploidy is also often associated with chromosomal instability (CIN), a more complex phenotype characterized by a higher rate of chromosome gains and losses during cell division, and hence a greater propensity for karyotypic change. [2, 17,18,19,20] CIN positive cells create progeny with variable aneuploid karyotypes [2, 17]. Significant evidence now exists demonstrating that aneuploidy promotes CIN under certain conditions and vice versa [21,22,23]. Genomic instability is a long-established hallmark of cancer, and compound aneuploidy and CIN are central to the heterogeneity observed within tumors [24]. These defects drive adaptation that results in tumor development, progression, and chemotherapeutic resistance [10, 11].
In this review, we provide an overview of recent developments in the understanding of the intimate relationship between mitotic machinery dysfunction and aneuploidy. We highlight novel insights into the molecular mechanisms that rectify errors caused by these dysfunctions, focusing our discussion on animal cells. Additionally, we explore recent studies detailing the immediate consequences of uncorrected errors on genomic stability when the mitotic error correction mechanisms fail and underscore the relevance of these to cancer.
The central events of mitosis
The central events of mitosis are sister chromatid separation from one another and their segregation to opposite ends of the dividing cell, and eventually into the nascent daughter cells. These events occur in a tightly coordinated manner that can be conceptually divided into distinct stages. The first is prophase during which chromosomes, rearranged into condensed rod-like structures, begin to partially lose the cohesion complexes that hold them together (known as cohesins), and to resolve the intertwined strands of DNA between the linked sister-chromatids (known as catenations). In cell types and organisms that harbor centrosomes, their separation starts during mid to late prophase. These structure act as spindle poles, providing hubs for the nucleation and organization of spindle microtubules, an event that continues into the second stage, prometaphase [25,26,27]. Spindle formation, attachment of the dividing sister chromatids to spindle microtubules and their eventual congression towards the equatorial plane of the dividing cell are the major events of prometaphase. This is facilitated by kinetochores, large macromolecular machines that assemble on each sister chromatid during mitosis and form not only the major site of interaction between spindle microtubules and chromatids, but also serve as major signaling hubs during mitosis [28, 29]. Prometaphase culminates in chromosome alignment at the spindle equator with each kinetochore attached to an opposing pole in a bioriented manner. Metaphase, the third stage, can be defined as the period of time between sister chromatid alignment and separation, and is dependent on the attenuation of the Spindle Assembly Checkpoint (SAC), a major quality control pathway that slows the release of cells from metaphase into the next step, anaphase, until all chromosomes are attached and bioriented [30,31,32]. The metaphase-anaphase transition is generally irreversible and marks the beginning of the end for mitosis. It is characterized by the dissolution of sister chromatid cohesion, inactivation of the SAC and of cyclin-dependent kinase 1, the major mitotic kinase. The now separated sister chromatids begin to move from each other to opposite poles of the spindle before the poles themselves begin to move apart, completing chromosome segregation and heralding the physical division of the cytoplasmic contents (cytokinesis) into nascent daughter cells.
New developments in the sources and solutions of mitotic errors
High temporal and high resolution imaging of mitotic cells has recently indicated that the number of chromosomes at risk of mis-segregation in non-transformed human cells is considerably higher than previously thought with one study putting mis-segregation estimates at 18% in control cells that increases to 44% with nocodazole treatment [33]. Aberrant functioning of mitotic structures and pathways is a major source of chromosome mis-segregation and thus aneuploidy. For example, centrosome amplification can lead to divisions with multi-polar spindles which increases the rate of chromosome mis-segregation [34, 35]; altered kinetochore-spindle dynamics result in mis-attachments that lead to mis-segregation [36]; sister chromatid cohesion defects can lead to premature segregation [37], as can aberrant SAC signaling [38]. All of these are associated with aneuploidy and cancer and have been expertly reviewed elsewhere [1, 39, 40]. We also refer the reader to Table 1 and the references within, for a more detailed description of the drivers of CIN. Below, we describe very recent studies that shed new light on the sources of chromosome segregation errors that lead to aneuploidy in cancer, and that describe new pathways active during cell division that control the fidelity of the genome through correcting errors in chromosome copies as well as errors in their safe delivery to the daughter cells.
Lagging and misaligned chromosomes as sources of aneuploidy
A hallmark of metazoan mitosis is the formation of a metaphase plate at the spindle equator, where sister chromatid pairs align and form connections with microtubules emanating from opposite spindle poles (termed bioriented or amphitelic attachment, Fig. 1A). This back-to-back geometry is the only one to ensure correct segregation of chromatids towards their respective poles. Other conformations including monotelic/mono-oriented (where only a single sister-kinetochore is connected to microtubules emerging from one pole, Fig. 1B), syntelic (where both sister kinetochores attach to the same pole, Fig. 1C) both activate the SAC and are corrected before anaphase onset. In addition to these, lateral attachments (where a kinetochore is attached to the lateral surface of a microtubule) are thought to form as an intermediate step before conversion into end-on attachments between kinetochores and microtubule ends [41]. When these unproductive attachments are detected, the so-called error correction pathway destabilizes them. Mechanistically, this pathway requires the activity of the centromere and kinetochore kinase Aurora B (AURKB), the catalytic subunit of the chromosomal passenger complex (CPC). AURKB is a central organizer of centromere structure and kinetochore function through spatially restricted phosphorylation of key substrates involved in maintaining the stability of kinetochore-microtubule attachments. This includes most notably the NDC80 homolog (NDC80 or HEC1) subunit of the major microtubule binding interface at the kinetochore, the KNL1-MIS12-NDC80 network, and the microtubule-depolymerizing kinesin mitotic centromere-associated kinesin (MCAK) [42, 43]. The unstructured N-terminal tail of HEC1 is overall positively charged [44] enabling direct interaction with negatively charged microtubules, thereby stabilizing their polymerizing ends [45]. AURKB phosphorylation reduces the tail’s positive charge, decreasing its affinity for microtubules, causing release of the attachment [44, 46,47,48] as well as stimulating microtubule depolymerization [45]. AURKB-phosphorylation of MCAK changes the kinesin’s conformation, reducing its microtubule affinity and depolymerization activity [49,50,51]. More recently, it was shown that AURKB phosphorylated MCAK in its microtubule binding region resulting in allosteric control and graded microtubule depolymerase activity [49]. In this manner, AURKB activity through phosphorylation of MCAK, NDC80 and additional substrates [52, 53], enables the kinetochore to release and reattach until the correct orientation is achieved. In line with this, alterations in AURKB activity have been repeatedly shown to result in an increase in improper attachments [54, 55].
Error-free chromosome segregation depends on the correct attachment of the sister kinetochores to microtubules associated with opposite spindle poles in an amphotelic (or bi-oriented) manner (A). Three major types of incorrect attachments have been observed: (B) Monotelic attachment occurs when only one of the sister-kinetochores is attached and to spindle microtubules, while the other remains unattached; (C) Syntelic attachments occur when both sister kinetochores attach to microtubules from a single pole; and (D) Merotelic attachments typically involve a single kinetochore attached to microtubules emerging from both poles. Figure generated with biorender.
Particularly detrimental to mitotic fidelity are merotelic attachments, in which a single or both sister-kinetochores bind microtubules from both spindle poles [56] (Fig. 1D). Although mostly corrected before anaphase by AURKB-mediated error correction, merotelic attachments are not efficiently detected by the SAC and a proportion of merotelic chromosomes remain stably tethered forming lagging chromosomes that fail to segregate during anaphase [57, 58]. Estimates suggest that between 0.1% and 10% of human primary, non-transformed, and chromosomally stable cancer cells progress into anaphase with one or few chromosomes lagging behind due to merotelic attachments [59,60,61,62]. Lagging chromosomes are thought to be a major cause of CIN in non-transformed cells [57, 60, 63] and in a subset of CIN-positive cancer cell lines [12, 64] as they can ultimately segregate to the incorrect daughter cell. This failure to segregate before the nuclear envelope reassembly (NER) can result in micronuclei (“Micronuclei”) that are prone to chromothripsis (“Chromothripsis”), or may initiate anaphase bridges that are eventually broken, initiating cycles of chromosome breakage and fusion known as “breakage fusion bridge” (BFB, “The chromosome breakage-fusion-bridge cycle”).
How lagging chromosomes form is unclear, but spindle geometry in early prometaphase [65,66,67] and hyperstabilization of kinetochore-microtubule interactions and dampened turnover dynamics [36, 68] have both been shown to increase incidences of merotely. Recently, elegant super resolution microscopy experiments demonstrated that the vertebrate centromere and kinetochore forms a bipartite structure resulting in two subdomains that independently associate with the spindle microtubules [69]. In amphitelic kinetochores, the subdomains are oriented in the same direction; however, merotelic kinetochores have bioriented subdomains, resulting in lagging chromosomes with highly stretched kinetochores. Importantly, merotelic attachments resulting from the biorientation of kinetochore subdomains occurred relatively frequently during cancer cell mitoses, indicating that they play a significant role in promoting CIN [69].
The proper biorientation and alignment of chromosomes at metaphase is generally monitored by the SAC; this infers that under normal physiological states, cells only transition to anaphase once all chromosomes align and biorient. However, recent evidence suggests that misaligned chromosomes that failed to completely align at metaphase before anaphase onset contribute to segregation errors and aneuploidy more frequently than previously thought. To explore mitotic and chromosome segregation defects that contribute to CIN in tumors, Tucker et al [70]. studied a panel of breast cancers and breast cancer cell lines. These authors demonstrated that misaligned chromosomes were the most predominant defects in primary and metastatic breast cancers (including primary-metastatic matched pairs) and that their presence correlated with the increase in CIN between primary and metastatic tumors. These observations were corroborated in patient-derived organoids and multiple human cancer cell lines [70, 71]. In a complementary study, Gomes et al [71]. systematically depleted 125 proteins involved in kinetochore-microtubule attachment including proteins that regulate attachment stability, attachment turnover and microtubule cross-linking, and investigated how human cells respond to the resulting chromosome segregation defects using high-content live-cell imaging. The authors found that, regardless of the underlying molecular defect, cells frequently entered anaphase with misaligned chromosomes that often subsequently mis-segregated, despite apparent satisfaction of the SAC [71]. In addition, these misaligned chromosomes were found to be a strong predictor of micronuclei formation. Consistent with the detrimental effects of widespread chromosome mis-segregation on viability, in both studies, the loss or gain of single chromosomes was observed at a significantly higher frequency than more widespread changes in cancer cell models [70, 71]. This could indicate that in these cells, SAC activation is not robust enough to prevent the metaphase-anaphase transition with single (or very few) unattached kinetochores [72, 73]. Alternatively, these results could reflect inappropriate silencing and inactivation of the SAC, and it will be important to distinguish between these two scenarios in the future. Moreover, although depletion of one of many proteins involved in maintaining correct kinetochore-microtubule attachment can result in mis-aligned chromosomes in cancer cells, the underlying defects at the site of attachment, including the attachment geometry, the conformation of the kinetochore subdomains, and the presence of merotelic attachments, remain to be explored.
AURKB-mediated in error correction during anaphase
As noted above, the error correction pathway mediated by AURKB is a major mechanism of rectifying aberrant (in particular merotelic and syntelic) attachments between spindle microtubules and kinetochores in early mitosis [54, 55, 74, 75]. The error correction activity of AURKB was thought to be limited to prometaphase. However, discrepancies between the rate of anaphase lagging chromosomes (approximately 5%) [12, 36, 61, 68] and the rate of chromosome mis-segregation in non-transformed human cells (approximately 1%) [76] hinted at the existence of an anaphase-specific mechanism to limit chromosome mis-segregation (Fig. 2A).
A Schematic overview of recent advances described in the present review, illustrated in association with the mitotic stages with which they are most associated. Segregation errors occur at the metaphase-anaphase transition as a result of merotelic attachment, chromosome fragmentation, DNA bridge or a weakened error correction system. The CIP2A-TOPBP1 complex act as a mitotic glue to cluster acentric chromosome fragments to limit chromosomal loss in prometaphase. During anaphase, an AURKB gradient will delay nuclear envelope reassembly around lagging chromosome to allow their reintegration into the main nuclei in anaphase. Non-resolved bridges, free acentric chromosome fragments or lagging chromosomes can induce micronuclei formation in late anaphase and telophase and leads to CIN, to an arrest of cell cycle or to cell death. B Schematic representation of mechanisms involved in panel A and discussed in the text: (i) Clustering of chromosome fragments and the role of the CIP2A-TOPBP1 complex in chromothripsis; (ii) Resolution of mitotic DNA damage by the TOPBP1-POLθ complex; (iii) (4) The role of micronuclei in propagating DNA damage, aneuploidy and CIN; and (iv) Representation of breakage fusion bridge cycle. Figure generated with biorender.
At the metaphase to anaphase transition, the CPC including AURKB relocates to the spindle midzone in a manner dependent on the kinesin protein Mitotic Kinesin-Like Protein 2 (MKLP2) [77], where it generates a phosphorylation gradient starting at the midzone that becomes progressively weaker towards the poles thus providing spatial information for events in anaphase and cytokinesis [78]. Initial work has suggested that this phospho-gradient delays chromosome decondensation and NER in response to incomplete chromosome segregation during anaphase [79]. More recently, three independent groups have collectively demonstrated additional roles for this gradient: maintenance of anaphase kinetochore structure over distance and time, and anaphase error correction of merotelic attachments.
In exploring the mechanisms of kinetochore stability in early anaphase, a critical timepoint in the transport of chromosomes, Papini and colleagues found that phosphorylation of the kinetochore substrate DSN1 Component Of MIS12 Kinetochore Complex (DSN1) was sensitive to its distance from midzone AURKB [80]. Specifically, midzone AURKB-mediated phosphorylation of S100/S109 of DSN1 reduced the rate at which DSN1 was lost from kinetochores as anaphase progressed, suggesting that the AURKB gradient may prolong kinetochore structure and microtubule attachment stability, specifically in anaphase. Because phosphorylation of S100/S109 of DSN1 in prometaphase destabilizes kinetochore-microtubule interactions, the level of AURKB gradient activity experienced by kinetochores in early anaphase could be sufficient to maintain DSN1 phosphorylation to stabilize kinetochores but may be insufficient to globally destabilize kinetochore-microtubule interactions as observed in pre-anaphase cells [81, 82].
In a complementary study Orr et al. found that while both CIN-, non-transformed (RPEI) and CIN+ transformed (U2OS) cells displayed transient lagging chromosomes during anaphase, a much smaller proportion of these events resulted in micronuclei formation in both cellular contexts, again suggesting that most lagging chromosomes are corrected during anaphase [83]. In investigating the role of AURKB in this error correction, the authors found that inhibition of AURKB catalytic activity or its delocalization from the central spindle by MKLP2 depletion or chemical inhibition abolished the formation of a phosphorylation gradient on both segregating and lagging chromosomes while significantly increasing the frequency of anaphase cells with lagging chromosomes and micronuclei [83]. Building on the role of AURKB in activating the pleiotropic mitotic kinase polo-like kinase 1 (PLK1) at kinetochores in early mitosis [84, 85], the authors found that active PLK1, a regulator of kinetochore-microtubule interactions in prometaphase [86], was specifically enriched at kinetochores of lagging chromosomes. This suggests that PLK1 is anaphase target of AURKB. Interestingly, correction of anaphase lagging chromosomes and their subsequent re-integration into the main nuclei were greatly compromised by partial RNAi-mediated depletion of additional key kinetochore proteins involved in the formation or regulation of microtubule attachments suggesting that AURKB may target additional proteins at anaphase kinetochores in conjunction with DSN1 and PLK1 to regulate stability of kinetochore-microtubule interactions. Overall, these two studies suggest that, although centromeric AURKB promotes microtubule detachment from kinetochores under low tension to correct errors in early mitosis, midzone-associated AURKB is required for the local stabilization of kinetochore-microtubule attachments necessary for efficient mechanical transduction of spindle forces involved in error correction during anaphase.
High resolution and high temporal imaging enabled the tracking of chromosomes in anaphase in the aforementioned studies. However, distinguishing truly lagging chromosomes from those that are late segregating constitutes a significant challenge in cell division research, as these classes of dividing chromosomes will likely have distinct fates. To address this issue, recent work employing a combination of lattice light-sheet live-cell imaging and computational analysis of chromosome segregation errors enabled a quantitative measure of chromosome lag, termed “laziness” that reflects the behavior of a single kinetochore throughout anaphase. Using this approach, the stretched presumably merotelic population of lazy kinetochores were found to persist in anaphase more frequently than the unstretched population, with incidences of 50% versus 14%, respectively [33]. These findings demonstrate how merotely is linked to lazy behavior and implied the presence of an error correction mechanism in anaphase capable of resolving such improper attachments. Building on the work of Papini et al. and Orr et al., Sen et al. observed a significant increase in laziness in cells where AURKB was inhibited after metaphase [33, 80, 83]. Lazy kinetochores failed to be corrected, and displayed severe kinetochore stretch in anaphase indicative of merotelic attachments. Ultimately inhibition of AURKB in anaphase or inhibition of its localization at the spindle midzone led to a significant increase in micronuclei formation indicating a direct link between anaphase error correction by AURKB and micronuclei formation. Overall, these studies are consistent with the idea that an AURKB gradient helps sustain kinetochore structure over the time and distance necessary for normal anaphase chromosome segregation and regulates kinetochore disassembly as cells enter telophase. This positional control of kinetochore phosphorylation may also facilitate kinetochore stability on lagging chromosomes to be maintained to promote their movement to the poles as they separate. Future work will be needed understand how these different characteristics of anaphase kinetochores are regulated by AURKB.
DNA damage repair during mitosis
DNA double strand breaks (DSBs) are highly deleterious lesions, and maintaining genome integrity depends on their efficient repair. The cell uses distinct repair mechanisms at various stages of the cell cycle to accomplish this. Non-homologous end joining (NHEJ) is primarily active during G1 and is linked to a checkpoint at the G1/S transition that delays progression into S phase in the presence of DNA damage [87,88,89]. Homologous recombination (HR), which requires a DNA template, is restricted to the S and G2 phases of the cell cycle, and is associated with the G2/M “DNA damage” checkpoint [87,88,89]. Despite these checkpoints, cells can still enter mitosis with unresolved DSBs [90]. DSBs can also arise during mitosis, due to replication stress, anaphase bridge breakage, or under-replicated DNA regions at common fragile sites [91,92,93,94,95]. While the major DNA repair pathways such as HR and NHEJ are generally inactive during mitosis, some evidence suggests that mitotic cells can stabilize chromosome breaks until they can be safely repaired in the following cell cycle. Recent work has suggested that mechanistically, this may involve non-canonical functions for the cellular inhibitor of PP2A (CIP2A)-DNA topoisomerase II binding protein 1 (TOPBP1) complex initially reported to promote the segregation of acentric or damaged chromosome fragments that arises from impaired DNA synthesis [96].
In interphase, CIP2A is actively exported from the nucleus restricting its interaction with nuclear proteins [96, 97]. During mitosis however, nuclear envelope breakdown releases nuclear proteins, including TOPBP1, allowing CIP2A-TOPBP1 complex formation and translocation to sites of DNA damage on mitotic chromosomes (Fig. 2Bi). Mechanistically, TOPBP1 can be recruited to DNA damage lesions in mitosis through direct interaction with Mediator of DNA damage checkpoint protein 1 (MDC1) [98] which, in turn, directly binds γH2AX-containing chromatin assembled at double-strand breaks [99]. CIP2A binds directly to TOPBP1 which mediates its recruitment to sites of DNA damage in mitosis [96, 97, 100]. The CIP2A-TOPBP1 complex at mitotic DSBs then stabilizes chromosomes by forming a tether between broken ends effectively preventing exposure of open DNA ends. The mechanism by which CIP2A–TOPBP1 tethers fragments is yet to be determined, but it may involve higher-order molecular interactions mediated by the extensive coiled-coil domain of CIP2A [96]. In addition, mitotic DNA lesions can recruit TOPBP1 and CIP2A in an MDC1 independent manner as well, and the role of MDC1 in mitotic tethering of broken DNA fragments remains to be clarified [98]. Regardless of the exact mechanism, these observation suggest that the CIP2A-TOPBP1 complex allows for the repair of DSBs during mitosis (described below) or at subsequent phases of the cell cycle where DNA damage can be repaired [96, 97]. In agreement with this, irradiated CIP2A-deficient mitotic cells displayed increased radiosensitivity, γH2AX foci—indicating unrepaired DNA damage—, spontaneous micronuclei formation, and DSB repair defects compared to irradiated wild-type cells. Importantly, these phenotypes were rescued by the re-expression of CIP2A [97].
The microhomology-mediated end-joining (MMEJ) pathway—previously considered to be a backup to HR and NHEJ—has emerged as a critical mechanism for mitotic DSB repair that relies on the activity of the CIP2A-TOPBP1 complex. Brambati et al. identified the RAD9 checkpoint clamp component A-HUS1 checkpoint clamp component-RAD1 checkpoint DNA exonuclease (RAD9A-HUS1-RAD1 or 9-1-1) complex and its interacting partner RAD9-HUS1-RAD1 interacting nuclear orphan 1 (RHINO) as key MMEJ factors. RHINO, which also functions in DNA damage sensing during replication [101], is stabilized during mitosis. The accumulation of RHINO subsequently facilitated mitotic DNA repair by binding to DNA polymerase theta (Polθ), a polymerase-helicase fusion protein that promotes MMEJ. Phosphorylation of RHINO by Polo-like kinase 1 (PLK1) during mitosis was found to be essential for its interaction with Polθ. PLK1 also directly phosphorylated and activated Polθ, which was then recruited to double-strand breaks (DSBs) to mediate the joining of broken DNA ends [102] (Fig. 2Bii). The TOPBP1-CIP2A complex plays an important role in this process; TOPBP1 interacts with and stabilizes RHINO at DSBs, promoting recruitment of Polθ to CIP2A-TOPBP1 complex-tethered DSBs [103]. In line with these observations, Polθ forms foci and filament-like structures during mitosis that colocalize with TOPBP1 foci, and TOPBP1 knockdown suppresses Polθ foci and filament structures. How TOPBP1 and Polθ interact is not clear, but one attractive hypothesis is that this may be occurring through a phospho-regulated interaction between Polθ and the BRCA1 DNA repair associated C-terminal (BRCT) domains of TOPBP1. Together, these studies establish MMEJ as a bona fide DSB repair pathway active during mitosis. Clearly, the resolution of mitotic DSBs and the tethering of acentric chromosome fragments are essential for genomic stability. Failure to resolve these breaks can result in lagging chromosome fragments, missegregation, micronuclei formation, and chromothripsis events [102, 104] as discussed below.
The earliest consequences of aneuploidy
The presence of robust mechanisms for monitoring genome fidelity in mitosis such as the AURKB error correction and MMEJ pathways described above, represent important defense mechanisms against cancer. Chromosome damage and imbalance can lead to cancer by introducing extra copies of oncogenes or deleting tumor suppressor genes. It can also result in generic stresses on the cell that are chromosome agnostic, including proteotoxic, metabolic and oxidative stress due to global increases in protein production, as summarized in numerous excellent reviews. [76, 105,106,107,108] Over the last decade, mitotic errors have been shown to drive the genesis of complex chromosomal aberrations, including the loss, gain, inversion, or translocation of chromosome fragments [109, 110]. These aberrations are common in human tumors and promote tumorigenesis by inducing further DNA damage, mutagenesis, and gene copy number changes [109]. Here, we describe recent advances in our understanding of the earliest known consequences of aberrant chromosome segregation that eventually lead to mutagenesis and the surveillance mechanisms they trigger.
Micronuclei
Mis-segregating chromosomes (or chromosome fragments) can be excluded from the nucleus when it reforms in the daughter cell and is instead packed into a small extranuclear structure called a micronucleus that persists into interphase. DNA trapped in micronuclei can become damaged, massively rearranged, and can exhibit altered epigenetic marks [111]. Accordingly, the presence of micronuclei is associated with an increased risk of many cancers and is generally a typical characteristic of many advanced cancers [112,113,114]. Micronuclei have drawn exceptional attention recently because of their causal link to complex genome arrangements including chromothripsis (Fig. 2Biii).
The nuclear envelopes of micronuclei harbor fragile areas with large gaps in the nuclear lamina meshwork and fewer nuclear pores, impairing the recruitment of proteins involved in DNA transcription, replication, and repair. [104, 115,116,117] These fragile membranes are also more prone to rupture, which can trigger inflammatory signaling [113, 118]. In addition to the nuclear membrane defects, micronuclear chromosomes themselves lack important kinetochore assembly factors like centromere proteins A, C and T, likely due to a general import defect [119]. This results in kinetochore defects in micronuclear chromatids and to further mis-segregation in the subsequent mitosis, promoting additional aneuploidy and CIN [119].
Various scenarios have been put forward to explain how nuclear envelopes of micronuclei can be damaged during their formation in anaphase. First, the spindle midzone that forms in anaphase between the segregated chromosomes contains a high density of microtubules, which could impair nuclear envelope assembly around mis-segregated chromosomes in this region [120]. Second, as indicated above, the spindle midzone exhibits elevated activity of both AURKB and PLK1. High AURKB activity at the spindle midzone may sense lagging chromosomes and inhibit nuclear envelope assembly to allow reincorporation of laggards. In agreement, inhibition of AURKB suppresses nuclear envelope defects [79, 121, 122]. Similarly, PLK1 activity may negatively regulate nuclear pore complex protein reincorporation into nuclear membranes in anaphase; elevated midzone PLK1 activity may thus prevent efficient NPC incorporation into the nascent membranes of lagging chromosomes [121].
Once formed, micronuclei have essentially four different fates: (1) they can persist as independent cytoplasmic structures (approximately 70% of micronuclei), (2) they can be reintegrated to the main nucleus during the next mitosis, (3) they can be transported to the extracellular environment by extrusion; or (4) they can be degraded by autophagy or by an apoptosis-like process [123, 124]. None of these fates are positive: persistence results in dysregulated gene expression and further genomic instability; extrusion or degradation results in aneuploidy; and nuclear reintegration of the damaged and rearranged micronuclear DNA can further exacerbate genomic instability [104, 124]. Fortunately, as recently shown, non-transformed cells are able to avoid these consequences as a result of cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway activation. Micronuclear envelope rupture exposes the DNA directly to the cytoplasm, activating the cytosolic DNA sensor cGAS. Its activation triggers a nuclear factor-κB-dependent type I interferon response called the senescence-associated secretory phenotype (SASP) via the adaptor protein STING. This activates the innate immune system, triggering an inflammatory response that induces cellular senescence and stimulates the clearance of senescent and cancerous cells [125,126,127,128]. Accordingly, cells with complex karyotypes display increased secretion of SASP-related cytokines (interleukin (IL)6, IL8, C-C motif chemokine ligand 2) that both induce senescence and recruit and activate immune cells [105, 129,130,131]. In this manner, cells with abnormal karyotypes signal for their own removal, as a means of cancer immunosurveillance.
Chromothripsis
Defective DNA replication and repair processes that occur in micronuclei can also induce chromosome shattering, resulting in further chromosomal rearrangements and formation of new derivative chromosomes through chromothripsis. This can involve the complete rearrangement of loci, translocations and changes in copy number and loss of tumor suppressor genes as well as the amplification of oncogenes [116, 117, 132, 133] Damaged chromosomes in micronuclei can even be pulverized into acentromeric fragments that lack spindle attachments and that could become unequally distributed between the daughter cells during the next division [104, 116, 134]. These fragments could induce further extensive genomic rearrangements and high gene copy number variations—characteristics of chromothripsis—eventually culminating in the presence of cytoplasmic DNA fragments that could activate the cCGAS-STING pathway.
The causes of chromothripsis are not well understood; however, one potential explanation for its emergence is the disruption of micronuclear envelopes. On the one hand, rupture of the micronuclear envelope could result in exposure of the contents to cytoplasmic nucleases such as three prime repair exonuclease 1 (TREX1), leading to chromosome fragmentation. TREX1 is known to degrade cytoplasmic DNA to avoid inappropriate innate immune activation [135,136,137]. On the other hand, and somewhat paradoxically, degradation of exposed DNA from ruptured micronuclei by TREX1 can decrease cGAS/STING pathway activation in cancer [138, 139]. Nevertheless, cells lacking TREX1 exhibit less complex genome rearrangement after induction of chromothripsis [132, 140,141,142,143,144]. Moreover, TREX1 is an endoplasmic reticulum-associated enzyme and upon micronuclei envelope rupture, endoplasmic reticulum tubules have been observed invading the chromatin of ruptured micronuclei suggesting that this enzyme is at the right time and place to degrade exposed DNA [117].
Two recent studies proposed a new model to describe the fates of pulverized chromosomes from micronuclei during the next mitosis that invokes an additional role for the CIP2A-TOBPI complex described above. Using different cell lines and approaches to generate micronucleated cells and chromothripsis, Lin et al. and Trivedi et al. both observed the clustering of acentric chromosome fragments in close spatial proximity throughout mitosis that subsequently and collectively segregated asymmetrically to one of the daughter cells in a consistent manner [145, 146]. This clustering was found to be dependent on the CIP2A-TOPBP1 complex as depletion of either TOPBP1 or CIP2A resulted in an increased proportion of cells with dispersed micronuclear chromosomal fragments in mitosis. Importantly, this was a mitosis-specific function of this complex as degradation of CIP2A in mitosis was sufficient to disperse micronuclear fragments, although loss of nucleocytoplasmic compartmentalization in ruptured micronuclei in interphase may already promote cytoplasmic CIP2A and nuclear TOPBP1 association with DNA lesions [145]. Absence of fragment tethering in mitotic cells lacking the CIP2A-TOPBP1 complex after induced micronucleation and transient CIP2A depletion resulted in an increase in both deletions and inversions compared to non-depleted counterparts, as well as activation of the cGAS-STING pathway and apoptosis-related transcriptional programmes. As a result, daughter cells deficient in CIP2A were predisposed to cell death during the subsequent interphase compared to control daughter cells [145, 146]. Overall, these studies demonstrated that CIP2A-TOPBP1-regulated tethering in mitosis may be critical for bulk segregation of most chromosome fragments to one of the daughter cells, suggesting minimal loss of genomic content in the remaining daughter cell. This phenomenon was coined “balanced chromothripsis” and is generally much less deleterious than the “canonical chromothripsis” described above, which is characterized by random fragment inheritance. Supporting this finding, pan cancer tumor genome analyses revealed that CIP2A and TOPBP1 expression was elevated in cancers with genomic rearrangements, including those exhibiting chromothripsis. In contrast, their expression was comparatively lower in cancers characterized by canonical chromothripsis, where deletions were more frequently observed.
The chromosome breakage-fusion-bridge cycle
The chromosome breakage-fusion-bridge (BFB) cycle is a mechanism of genome instability that occurs as consequence of chromosome bridge breakage (Fig. 2Biv). Chromosome bridges are double-stranded chromatin fibres connecting the segregated chromosome masses in anaphase and can persist in the daughter nuclei in telophase and the following interphase if not adequately resolved. Chromosome bridges can be a consequence of DNA breakage, merotelic attachments, incomplete DNA replication, or incorrect resolution of chromosome catenation, and are a defining characteristic of dicentric chromosomes - chromosomes with two active centromeres [147]. In the case of dicentric centromeres, attachment of spindle microtubules to kinetochores on each of the two centromeres would result in segregation of the dicentrics towards opposite poles thereby generating chromatin bridges, breakage of which can lead to fusion of ends during the next interphase to recreate new dicentrics, engaging cells in recurrent BFB cycles. The BFB cycle can thus induce structural rearrangements such as telomere deletion and gene inversion, translocation, duplication, and loss [148, 149]. This cycle has, for example, been reported to fuel tumorigenesis by amplifying oncogenes including CDK4, cyclin E1, MDM2, EGFR, MYC, and ERBB2 [150, 151].
In animal cells, blocking cytokinesis after chromosome segregation prevents dicentric breakage [152], but the mechanisms involved in chromosome bridge breakage are unclear and a number of different hypotheses have been explored to explain this. One study suggested that stretching of chromosome bridges in the interphase following the aberrant division - now surrounded by both nuclear and plasma membrane- could result in frequent nuclear envelope ruptures and would expose the DNA to cytoplasmic nucleases such TREX1, resulting in DNA damage that promotes chromothripsis [132]. However, a separate study indicated that knockout of TREX1 did not delay bridge cleavage, suggesting the existence of TREX1-independent breakage mechanisms [153]. Instead, cellular tension across the bridge was found to be necessary to for bridge breakages and a critical role for cytoplasmic actomyosin contractile forces in inducing bridge extension and breakage was proposed. By using single-cell whole genome sequencing techniques, reciprocal chromosome segment gain and loss patterns in the daughter cells were identified after bridge breakage [153]. Not surprisingly, genome rearrangements were detected near the breakage point, a consequence of local chromosome fragmentation and defective repair and replication of bridged DNA from previous cycles. These errors could induce a second wave of DNA damage in the mitosis following a bridge breakage, leading to further micronuclei formation and chromothripsis. Because micronuclei can harbor centromeric fragments, the stretching required to break chromosome bridges could induce the stripping of centromeric proteins resulting in compromised centromere and kinetochore functions, consistent with previous observations of stretching-induced histone ejection from DNA [132, 154]. Taken together, these studies reveal that breakage of even a single chromosome bridge can have severe consequences for genome stability and the acceleration of karyotype evolution.
A p53-dependent mitotic surveillance mechanism
As previously discussed, mitotic defects that escape detection and repair result in misaligned and anaphase lagging chromosomes prone to micronuclei formation and further genomic insults. In normal, non-transformed cells, the presence of mitotic defects triggers a tumor protein p53 (TP53/ p53)-dependent reduction in cell proliferation [1, 12, 105, 155,156,157,158,159]. Striking discoveries over the last decade has revealed an additional mitotic defect to which the p53 pathway responds: prolonged mitotic timing, even in the absence of detectable defects.
P53 protein, known as the “Guardian of the genome”, is a well-known protein involved in the protection of the cells from cellular damage by regulating gene expression to control DNA repair, cell division and cell death. Upon its activation in response to a range of genomic insults, p53 translocate to the nucleus to bind to the cyclin dependent kinase inhibitor 1 A (CDKN1A) promoter. This upregulates the transcription of CDKN1A (known as p21), which then binds to cyclin E/cyclin-dependent kinase (CDK)2 and cyclin D/CDK4 to arrest the cell cycle in G1 [160, 161].
Initial studies linking M phase and the p53 activation in the following cell cycle found that a prolonged prometaphase arrest longer than 90 minutes in non-transformed RPE1 cells induced a cell cycle arrest in the next G1, even in healthy, error-free cell divisions. Depletion of p53 allowed cells to proliferate, regardless of mitotic delay [162]. Building on these findings, Lambrus et al. demonstrated that depletion of polo-like kinase 4, a regulator of centriole biogenesis, triggered a p53-dependent cell cycle arrest independently of the presence of segregation errors [163]. In a CRISPR/Cas9 knockout screen, the authors identified that the cell cycle arrest caused by centrosome loss, or an extended prometaphase was dependent on the USP28–53BP1–p53–p21 pathway (also called the mitotic stopwatch complex). This complex consists of tumor protein p53 binding protein 1, which recruits p53, and ubiquitin specific peptidase 28, which stabilizes p53 via deubiquitination [164]. More recently, Meitinger et al. further extrapolated on these results and demonstrated that the length of mitosis is tracked by the mitotic kinase PLK1, which regulates the assembly of stopwatch complexes that are transmitted between daughter cells. The complex persists into G1, leading to increased p21 transcription, cell cycle arrest, and induction of senescence in response to a single significantly extended mitosis or successive modestly extended mitoses [165]. Collectively, these data indicated that the mitotic stopwatch complex –a biochemical memory signal - forms only when mitosis is prolonged. The accumulation of this complex progressively rises during prolonged mitosis in a PLK1-dependent manner, is passed on to daughter cells, and remains stable enough to preserve the memory of extended mitoses. Unsurprisingly, the genes encoding the three stopwatch complex subunits are classified tumor suppressors [166]. Compromised stopwatch function was associated not only with p53 mutant cancers, but also a substantial proportion of p53 wild-type human cancers. Stopwatch status also influenced the efficacy of anti-mitotic drugs that functioned by prolonging mitosis, with attenuated stopwatch function being permissive to cell proliferation after treatment. The stopwatch complex may thus function as an additional genome ‘fidelity filter’ that halts the proliferation of potentially deleterious cells that would otherwise pass mitotic checkpoints such as the SAC.
Conclusion and perspectives
Over the last decade, our comprehension of how different errors in mitosis arise, the mechanisms that surveil and correct them, and the consequences to the genome should these mechanisms fail has evolved rapidly. Although the classical mitotic surveillance pathways, such as the SAC and the error correction pathway remain the best understood, recent research has revealed how lingering prometaphase errors are corrected in anaphase, how prolonged mitosis triggers a biochemical alarm that halts daughter cell proliferation, and how certain chromosome breaks are repaired in mitosis. Alternative variants and isoforms of key mitotic proteins are being identified in normal and cancer genomes and the consequences of their expression to mitotic fidelity will need to be systematically explored [167, 168]. We also have a better understanding of how segregation errors induce complex genome rearrangements that serve as continual sources of CIN (Fig. 2A), and the development of new sequencing approaches and analysis pipelines is likely to further revolutionize our understanding of the nature of the complex genome arrangements in cancer [169, 170]. Nevertheless, many questions remain: Are there any additional mechanisms that protect against chromosome mis-segregation in mitosis and its effects in the following G1? Activation of the p53 pathways is certainly a major mechanism although recent work suggested that arrest in G1 in response to mitotic errors can occur independently of p53 [171, 172]. What are the major types of chromosomes mis-segregation errors leading to micronuclei formation? Significant efforts have highlighted the contribution of merotelic attachments but the contribution of other attachments geometries remains to be further explored. Are there any additional clinically relevant consequences to chromosome segregation errors? Evolving technological approaches and innovative analysis pipelines will help answer these questions and will ultimately allow for leveraging of this information to effectively target aneuploidy and CIN in cancers.
References
Thompson SL, Bakhoum SF, Compton DA. Mechanisms of chromosomal instability. Curr Biol. 2010;20:R285–R295.
Holland AJ, Cleveland DW. Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis. Nat Rev Mol Cell Biol. 2009;10:478–87.
Taylor AM, Shih J, Ha G, Gao GF, Zhang X, Berger AC, et al. Genomic and functional approaches to understanding cancer aneuploidy. Cancer Cell. 2018;33:676–689.e3.
Lennartz M, Minner S, Brasch S, Wittmann H, Paterna L, Angermeier K, et al. The Combination of DNA Ploidy Status and PTEN/6q15 deletions provides strong and independent prognostic information in prostate cancer. Clin Cancer Res. 2016;22:2802–11.
Choma D, Daurès JP, Quantin X, Pujol JL. Aneuploidy and prognosis of non-small-cell lung cancer: a meta-analysis of published data. Br J Cancer. 2001;85:14–22.
Walther A, Houlston R, Tomlinson I. Association between chromosomal instability and prognosis in colorectal cancer: a meta-analysis. Gut. 2008;57:941–50.
DeSantis CE, Ma J, Goding Sauer A, Newman LA, Jemal A. Breast cancer statistics, 2017, racial disparity in mortality by state. CA Cancer J Clin. 2017;67:439–48.
Sansregret L, Swanton C. The role of aneuploidy in cancer evolution. Cold Spring Harb Perspect Med. 2017;7:a028373.
Weaver BA, Cleveland DW. The aneuploidy paradox in cell growth and tumorigenesis. Cancer Cell. 2008;14:431–3.
Ippolito MR, Martis V, Martin S, Tijhuis AE, Hong C, Wardenaar R, et al. Gene copy-number changes and chromosomal instability induced by aneuploidy confer resistance to chemotherapy. Dev Cell. 2021;56:2440–2454.e6.
Lukow DA, Sausville EL, Suri P, Chunduri NK, Wieland A, Leu J, et al. Chromosomal instability accelerates the evolution of resistance to anti-cancer therapies. Dev Cell. 2021;56:2427–2439.e4.
Thompson SL, Compton DA. Examining the link between chromosomal instability and aneuploidy in human cells. J Cell Biol. 2008;180:665–72.
Bakhoum SF, Danilova OV, Kaur P, Levy NB, Compton DA. Chromosomal instability substantiates poor prognosis in patients with diffuse large B-cell lymphoma. Clin Cancer Res. 2011;17:7704–11.
Burrell RA, McClelland SE, Endesfelder D, Groth P, Weller MC, Shaikh N, et al. Replication stress links structural and numerical cancer chromosomal instability. Nature. 2013;494:492–6.
Forment JV, Kaidi A, Jackson SP. Chromothripsis and cancer: causes and consequences of chromosome shattering. Nat Rev Cancer. 2012;12:663–70.
Storchova Z, editor. Aneuploidy in Health and Disease [Internet]. InTech; 2012 [cited 2024 Jun 16]. Available from: http://www.intechopen.com/books/aneuploidy-in-health-and-disease.
Chunduri NK, Storchová Z. The diverse consequences of aneuploidy. Nat Cell Biol. 2019;21:54–62.
Gordon DJ, Resio B, Pellman D. Causes and consequences of aneuploidy in cancer. Nat Rev Genet. 2012;13:189–203.
Nicholson JM, Cimini D. Link between aneuploidy and chromosome instability. In: International Review of Cell and Molecular Biology. Elsevier; 2015. p. 299–317. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1937644814000100.
Schukken KM, Foijer F. CIN and aneuploidy: different concepts, different consequences. BioEssays. 2018;40:1700147.
Nicholson JM, Macedo JC, Mattingly AJ, Wangsa D, Camps J, Lima V, et al. Chromosome mis-segregation and cytokinesis failure in trisomic human cells. Elife. 2015;4:e05068.
Reish O, Regev M, Kanesky A, Girafi S, Mashevich M. Sporadic aneuploidy in PHA-stimulated lymphocytes of trisomies 21, 18, and 13. Cytogenet Genome Res. 2011;133:184–9.
Garribba L, De Feudis G, Martis V, Galli M, Dumont M, Eliezer Y, et al. Short-term molecular consequences of chromosome mis-segregation for genome stability. Nat Commun. 2023;14:1353.
Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov. 2022;12:31–46.
Hinchcliffe EH, Sluder G. It takes two to tango”: understanding how centrosome duplication is regulated throughout the cell cycle. Genes Dev. 2001;15:1167–81.
Gomes Pereira S, Dias Louro MA, Bettencourt-Dias M. Biophysical and quantitative principles of centrosome biogenesis and structure. Annu Rev Cell Dev Biol. 2021;37:43–63.
McIntosh JR. Mitosis. Cold Spring Harb Perspect Biol. 2016;8:a023218.
Cheeseman IM, Desai A. Molecular architecture of the kinetochore–microtubule interface. Nat Rev Mol Cell Biol. 2008;9:33–46.
Cheeseman IM. The Kinetochore. Cold Spring Harb Perspect Biol. 2014;6:a015826–a015826.
Pachis ST, Kops GJPL. Leader of the SAC: molecular mechanisms of Mps1/TTK regulation in mitosis. Open Biol. 2018;8:180109.
von Schubert C, Cubizolles F, Bracher JM, Sliedrecht T, Kops GJPL, Nigg EA. Plk1 and Mps1 cooperatively regulate the spindle assembly checkpoint in human cells. Cell Rep. 2015;12:66–78.
Ikeda M, Tanaka K. Plk1 bound to Bub1 contributes to spindle assembly checkpoint activity during mitosis. Sci Rep. 2017;7:8794.
Sen O, Harrison JU, Burroughs NJ, McAinsh AD. Kinetochore life histories reveal an Aurora-B-dependent error correction mechanism in anaphase. Dev Cell. 2021;56:3082–e5.
Basto R, Brunk K, Vinadogrova T, Peel N, Franz A, Khodjakov A, et al. Centrosome amplification can initiate tumorigenesis in flies. Cell. 2008;133:1032–42.
Maiato H, Logarinho E. Mitotic spindle multipolarity without centrosome amplification. Nat Cell Biol. 2014;16:386–94.
Bakhoum SF, Thompson SL, Manning AL, Compton DA. Genome stability is ensured by temporal control of kinetochore–microtubule dynamics. Nat Cell Biol. 2009;11:27–35.
Barber TD, McManus K, Yuen KWY, Reis M, Parmigiani G, Shen D, et al. Chromatid cohesion defects may underlie chromosome instability in human colorectal cancers. Proc Natl Acad Sci USA. 2008;105:3443–8.
Barbosa J, Nascimento AV, Faria J, Silva P, Bousbaa H. The spindle assembly checkpoint: perspectives in tumorigenesis and cancer therapy. Front Biol. 2011;6:147–55.
Li R, Zhu J. Effects of aneuploidy on cell behaviour and function. Nat Rev Mol Cell Biol. 2022;23:250–65.
Vasudevan A, Schukken KM, Sausville EL, Girish V, Adebambo OA, Sheltzer JM. Aneuploidy as a promoter and suppressor of malignant growth. Nat Rev Cancer. 2021;21:89–103.
Tanaka K. Dynamic regulation of kinetochore-microtubule interaction during mitosis. J Biochem. 2012;152:415–24.
Ali A, Stukenberg PT. Aurora kinases: generators of spatial control during mitosis. Front Cell Dev Biol. 2023;11:1139367.
Krenn V, Musacchio A. The Aurora B Kinase in Chromosome Bi-Orientation and Spindle Checkpoint Signaling. Front Oncol. 2015;5. Available from: http://journal.frontiersin.org/Article/10.3389/fonc.2015.00225/abstract.
Ciferri C, Pasqualato S, Screpanti E, Varetti G, Santaguida S, Dos Reis G, et al. Implications for kinetochore-microtubule attachment from the structure of an engineered Ndc80 complex. Cell. 2008;133:427–39.
Umbreit NT, Gestaut DR, Tien JF, Vollmar BS, Gonen T, Asbury CL, et al. The Ndc80 kinetochore complex directly modulates microtubule dynamics. Proc Natl Acad Sci USA. 2012;109:16113–8.
DeLuca JG, Gall WE, Ciferri C, Cimini D, Musacchio A, Salmon ED. Kinetochore microtubule dynamics and attachment stability are regulated by Hec1. Cell. 2006;127:969–82.
Cheeseman IM, Chappie JS, Wilson-Kubalek EM, Desai A. The conserved KMN network constitutes the core microtubule-binding site of the kinetochore. Cell. 2006;127:983–97.
DeLuca KF, Lens SMA, DeLuca JG. Temporal changes in Hec1 phosphorylation control kinetochore–microtubule attachment stability during mitosis. J Cell Sci. 2011;124:622–34.
McHugh T, Zou J, Volkov VA, Bertin A, Talapatra SK, Rappsilber J, et al. The depolymerase activity of MCAK shows a graded response to Aurora B kinase phosphorylation through allosteric regulation. J Cell Sci. 2019;132:jcs228353.
Andrews PD, Ovechkina Y, Morrice N, Wagenbach M, Duncan K, Wordeman L, et al. Aurora B regulates MCAK at the mitotic centromere. Dev Cell. 2004;6:253–68.
Lan W, Zhang X, Kline-Smith SL, Rosasco SE, Barrett-Wilt GA, Shabanowitz J, et al. Aurora B phosphorylates centromeric MCAK and regulates its localization and microtubule depolymerization activity. Curr Biol. 2004;14:273–86.
Conti D, Gul P, Islam A, Martín-Durán JM, Pickersgill RW, Draviam VM. Kinetochores attached to microtubule-ends are stabilised by Astrin bound PP1 to ensure proper chromosome segregation. eLife. 2019;8:e49325.
Chan YW, Jeyaprakash AA, Nigg EA, Santamaria A. Aurora B controls kinetochore-microtubule attachments by inhibiting Ska complex-KMN network interaction. J Cell Biol. 2012;196:563–71.
Lampson MA, Renduchitala K, Khodjakov A, Kapoor TM. Correcting improper chromosome–spindle attachments during cell division. Nat Cell Biol. 2004;6:232–7.
Cimini D, Wan X, Hirel CB, Salmon ED. Aurora kinase promotes turnover of kinetochore microtubules to reduce chromosome segregation errors. Curr Biol. 2006;16:1711–8.
Duensing S. A tentative classification of centrosome abnormalities in cancer. Cell Biol Int. 2005;29:352–9.
Cimini D, Cameron LA, Salmon ED. Anaphase spindle mechanics prevent mis-segregation of merotelically oriented chromosomes. Curr Biol. 2004;14:2149–55.
Gregan J, Polakova S, Zhang L, Tolić-Nørrelykke IM, Cimini D. Merotelic kinetochore attachment: causes and effects. Trends Cell Biol. 2011;21:374–81.
Cimini D, Fioravanti D, Salmon ED, Degrassi F. Merotelic kinetochore orientation versus chromosome mono-orientation in the origin of lagging chromosomes in human primary cells. J Cell Sci. 2002;115:507–15.
Thompson SL, Compton DA. Chromosome missegregation in human cells arises through specific types of kinetochore–microtubule attachment errors. Proc Natl Acad Sci USA. 2011;108:17974–8.
Worrall JT, Tamura N, Mazzagatti A, Shaikh N, Van Lingen T, Bakker B, et al. Non-random Mis-segregation of human chromosomes. Cell Rep. 2018;23:3366–80.
Bakhoum SF, Kabeche L, Murnane JP, Zaki BI, Compton DA. DNA-damage response during mitosis induces whole-chromosome missegregation. Cancer Discov. 2014;4:1281–9.
Cimini D, Howell B, Maddox P, Khodjakov A, Degrassi F, Salmon ED. Merotelic kinetochore orientation is a major mechanism of aneuploidy in mitotic mammalian tissue cells. J Cell Biol. 2001;153:517–28.
Gascoigne KE, Taylor SS. Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs. Cancer Cell. 2008;14:111–22.
Kaseda K, McAinsh AD, Cross RA. Dual pathway spindle assembly increases both the speed and the fidelity of mitosis. Biol Open. 2012;1:12–18.
Marco E, Dorn JF, Hsu Phsin, Jaqaman K, Sorger PK, Danuser G. S. cerevisiae Chromosomes Biorient via Gradual Resolution of Syntely between S Phase and Anaphase. Cell. 2013;154:1127–39.
Silkworth WT, Nardi IK, Paul R, Mogilner A, Cimini D. Timing of centrosome separation is important for accurate chromosome segregation. Mol Biol Cell. 2012;23:401–11.
Bakhoum SF, Genovese G, Compton DA. Deviant kinetochore microtubule dynamics underlie chromosomal instability. Curr Biol. 2009;19:1937–42.
Sacristan C, Samejima K, Ruiz LA, Deb M, Lambers MLA, Buckle A, et al. Vertebrate centromeres in mitosis are functionally bipartite structures stabilized by cohesin. Cell. 2024;187:3006–3023.e26.
Tucker JB, Bonema SC, García-Varela R, Denu RA, Hu Y, McGregor SM, et al. Misaligned chromosomes are a major source of chromosomal instability in breast cancer. Cancer Res Commun. 2023;3:54–65.
Gomes AM, Orr B, Novais-Cruz M, De Sousa F, Macário-Monteiro J, Lemos C, et al. Micronuclei from misaligned chromosomes that satisfy the spindle assembly checkpoint in cancer cells. Curr Biol. 2022;32:4240–4254.e5.
Collin P, Nashchekina O, Walker R, Pines J. The spindle assembly checkpoint works like a rheostat rather than a toggle switch. Nat Cell Biol. 2013;15:1378–85.
Heinrich S, Geissen EM, Kamenz J, Trautmann S, Widmer C, Drewe P, et al. Determinants of robustness in spindle assembly checkpoint signalling. Nat Cell Biol. 2013;15:1328–39.
Ditchfield C, Johnson VL, Tighe A, Ellston R, Haworth C, Johnson T, et al. Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores. J Cell Biol. 2003;161:267–80.
Hauf S, Cole RW, LaTerra S, Zimmer C, Schnapp G, Walter R, et al. The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore–microtubule attachment and in maintaining the spindle assembly checkpoint. J Cell Biol. 2003;161:281–94.
Santaguida S, Amon A. Aneuploidy triggers a TFEB-mediated lysosomal stress response. Autophagy. 2015;11:2383–4.
Gruneberg U, Neef R, Honda R, Nigg EA, Barr FA. Relocation of Aurora B from centromeres to the central spindle at the metaphase to anaphase transition requires MKlp2. J Cell Biol. 2004;166:167–72.
Fuller BG, Lampson MA, Foley EA, Rosasco-Nitcher S, Le KV, Tobelmann P, et al. Midzone activation of aurora B in anaphase produces an intracellular phosphorylation gradient. Nature. 2008;453:1132–6.
Afonso O, Matos I, Pereira AJ, Aguiar P, Lampson MA, Maiato H. Feedback control of chromosome separation by a midzone Aurora B gradient. Science. 2014;345:332–6.
Papini D, Levasseur MD, Higgins JMG. The Aurora B gradient sustains kinetochore stability in anaphase. Cell Rep. 2021;37:109818.
Petrovic A, Keller J, Liu Y, Overlack K, John J, Dimitrova YN, et al. Structure of the MIS12 complex and molecular basis of its interaction with CENP-C at human kinetochores. Cell. 2016;167:1028–1040.e15.
Yatskevich S, Yang J, Bellini D, Zhang Z, Barford D. Structure of the human outer kinetochore KMN network complex. Nat Struct Mol Biol. 2024;31:874–83.
Orr B, De Sousa F, Gomes AM, Afonso O, Ferreira LT, Figueiredo AC, et al. An anaphase surveillance mechanism prevents micronuclei formation from frequent chromosome segregation errors. Cell Rep. 2021;37:109783.
Combes G, Alharbi I, Braga LG, Elowe S. Playing polo during mitosis: PLK1 takes the lead. Oncogene. 2017;36:4819–27.
Singh P, Pesenti ME, Maffini S, Carmignani S, Hedtfeld M, Petrovic A, et al. BUB1 and CENP-U, Primed by CDK1, Are the Main PLK1 kinetochore receptors in mitosis. Mol Cell. 2021;81:67–87.e9.
Elowe S, Hümmer S, Uldschmid A, Li X, Nigg EA. Tension-sensitive Plk1 phosphorylation on BubR1 regulates the stability of kinetochore–microtubule interactions. Genes Dev. 2007;21:2205–19.
Iyama T, Wilson DM. DNA repair mechanisms in dividing and non-dividing cells. DNA Repair. 2013;12:620–36.
Aparicio T, Baer R, Gautier J. DNA double-strand break repair pathway choice and cancer. DNA Repair. 2014;19:169–75.
Branzei D, Foiani M. Regulation of DNA repair throughout the cell cycle. Nat Rev Mol Cell Biol. 2008;9:297–308.
Deckbar D, Birraux J, Krempler A, Tchouandong L, Beucher A, Walker S, et al. Chromosome breakage after G2 checkpoint release. J Cell Biol. 2007;176:749–55.
Fragkos M, Naim V. Rescue from replication stress during mitosis. Cell Cycle. 2017;16:613–33.
Liu Y, Nielsen CF, Yao Q, Hickson ID. The origins and processing of ultra fine anaphase DNA bridges. Curr Opin Genet Dev. 2014;26:1–5.
Mankouri HW, Huttner D, Hickson ID. How unfinished business from S-phase affects mitosis and beyond. EMBO J. 2013;32:2661–71.
Le Beau M. Replication of a common fragile site, FRA3B, occurs late in S phase and is delayed further upon induction: implications for the mechanism of fragile site induction. Hum Mol Genet. 1998;7:755–61.
Zeman MK, Cimprich KA. Causes and consequences of replication stress. Nat Cell Biol. 2014;16:2–9.
Adam S, Rossi SE, Moatti N, De Marco Zompit M, Xue Y, Ng TF, et al. The CIP2A–TOPBP1 axis safeguards chromosome stability and is a synthetic lethal target for BRCA-mutated cancer. Nat Cancer. 2021;2:1357–71.
De Marco Zompit M, Esteban MT, Mooser C, Adam S, Rossi SE, Jeanrenaud A, et al. The CIP2A-TOPBP1 complex safeguards chromosomal stability during mitosis. Nat Commun. 2022;13:4143.
Leimbacher PA, Jones SE, Shorrocks AMK, De Marco Zompit M, Day M, Blaauwendraad J, et al. MDC1 interacts with TOPBP1 to maintain chromosomal stability during mitosis. Mol Cell. 2019;74:571–583.e8.
Stucki M, Clapperton JA, Mohammad D, Yaffe MB, Smerdon SJ, Jackson SP. MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks. Cell. 2005;123:1213–26.
Laine A, Nagelli SG, Farrington C, Butt U, Cvrljevic AN, Vainonen JP, et al. CIP2A interacts with TopBP1 and drives basal-like breast cancer tumorigenesis. Cancer Res. 2021;81:4319–31.
Cotta-Ramusino C, McDonald ER, Hurov K, Sowa ME, Harper JW, Elledge SJ. A DNA damage response screen identifies RHINO, a 9-1-1 and TopBP1 interacting protein required for ATR signaling. Science. 2011;332:1313–7.
Gelot C, Kovacs MT, Miron S, Mylne E, Haan A, Boeffard-Dosierre L, et al. Polθ is phosphorylated by PLK1 to repair double-strand breaks in mitosis. Nature. 2023;621:415–22.
Brambati A, Sacco O, Porcella S, Heyza J, Kareh M, Schmidt JC, et al. RHINO directs MMEJ to repair DNA breaks in mitosis. Science. 2023;381:653–60.
Crasta K, Ganem NJ, Dagher R, Lantermann AB, Ivanova EV, Pan Y, et al. DNA breaks and chromosome pulverization from errors in mitosis. Nature. 2012;482:53–58.
Santaguida S, Richardson A, Iyer DR, M’Saad O, Zasadil L, Knouse KA, et al. Chromosome mis-segregation generates cell-cycle-arrested cells with complex karyotypes that are eliminated by the immune system. Dev Cell. 2017;41:638–651.e5.
Oromendia AB, Dodgson SE, Amon A. Aneuploidy causes proteotoxic stress in yeast. Genes Dev. 2012;26:2696–708.
Torres EM, Sokolsky T, Tucker CM, Chan LY, Boselli M, Dunham MJ, et al. Effects of aneuploidy on cellular physiology and cell division in haploid yeast. Science. 2007;317:916–24.
Santaguida S, Vasile E, White E, Amon A. Aneuploidy-induced cellular stresses limit autophagic degradation. Genes Dev. 2015;29:2010–21.
Janssen A, Van Der Burg M, Szuhai K, Kops GJPL, Medema RH. Chromosome segregation errors as a cause of DNA damage and structural chromosome aberrations. Science. 2011;333:1895–8.
Levine MS, Holland AJ. The impact of mitotic errors on cell proliferation and tumorigenesis. Genes Dev. 2018;32:620–38.
Agustinus AS, Al-Rawi D, Dameracharla B, Raviram R, Jones BS, Stransky S. et al. Epigenetic dysregulation from chromosomal transit in micronuclei. Nature. 2023;619:176–83.
Bonassi S, Znaor A, Ceppi M, Lando C, Chang WP, Holland N, et al. An increased micronucleus frequency in peripheral blood lymphocytes predicts the risk of cancer in humans. Carcinogenesis. 2006;28:625–31.
Di Bona M, Bakhoum SF. Micronuclei and Cancer. Cancer Discov. 2024;14:214–26.
Guscott M, Saha A, Maharaj J, McClelland SE. The multifaceted role of micronuclei in tumour progression: a whole organism perspective. Int J Biochem Cell Biol. 2022;152:106300.
Okamoto A, Utani KI, Shimizu N. DNA replication occurs in all lamina positive micronuclei, but never in lamina negative micronuclei. Mutagenesis. 2012;27:323–7.
Zhang CZ, Spektor A, Cornils H, Francis JM, Jackson EK, Liu S, et al. Chromothripsis from DNA damage in micronuclei. Nature. 2015;522:179–84.
Hatch EM, Fischer AH, Deerinck TJ, Hetzer MW. Catastrophic nuclear envelope collapse in cancer cell micronuclei. Cell. 2013;154:47–60.
Kwon M, Leibowitz ML, Lee JH. Small but mighty: the causes and consequences of micronucleus rupture. Exp Mol Med. 2020;52:1777–86.
Soto M, García-Santisteban I, Krenning L, Medema RH, Raaijmakers JA. Chromosomes trapped in micronuclei are liable to segregation errors. J Cell Sci. 2018;13:jcs.214742.
Liu S, Kwon M, Mannino M, Yang N, Renda F, Khodjakov A, et al. Nuclear envelope assembly defects link mitotic errors to chromothripsis. Nature. 2018;561:551–5.
de Castro IJ, Gil RS, Ligammari L, Giacinto MLD, Vagnarelli P. CDK1 and PLK1 coordinate the disassembly and reassembly of the nuclear envelope in vertebrate mitosis. Oncotarget. 2018;9:7763.
Karg T, Warecki B, Sullivan W. Aurora B–mediated localized delays in nuclear envelope formation facilitate inclusion of late-segregating chromosome fragments. Mol Biol Cell. 2015;26:2227–41.
Shimizu N, Shimura T, Tanaka T. Selective elimination of acentric double minutes from cancer cells through the extrusion of micronuclei. Mutat Res/Fundamental Mol Mech Mutagenesis. 2000;448:81–90.
Hintzsche H. Fate of micronuclei and micronucleated cells. Mutation Res. 2017;771:85–98.
Yang H, Wang H, Ren J, Chen Q, Chen ZJ. cGAS is essential for cellular senescence. Proc Natl Acad Sci USA. 2017;114. Available from: https://doi.org/10.1073/pnas.1705499114.
Chien Y, Scuoppo C, Wang X, Fang X, Balgley B, Bolden JE, et al. Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity. Genes Dev. 2011;25:2125–36.
Jing H, Kase J, Dörr JR, Milanovic M, Lenze D, Grau M, et al. Opposing roles of NF-κB in anti-cancer treatment outcome unveiled by cross-species investigations. Genes Dev. 2011;25:2137–46.
Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature. 2007;445:656–60.
Mackenzie KJ, Carroll P, Martin CA, Murina O, Fluteau A, Simpson DJ, et al. cGAS surveillance of micronuclei links genome instability to innate immunity. Nature. 2017;548:461–5.
Dou Z, Ghosh K, Vizioli MG, Zhu J, Sen P, Wangensteen KJ, et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature. 2017;550:402–6.
Gao M, He Y, Tang H, Chen X, Liu S, Tao Y. cGAS/STING: novel perspectives of the classic pathway. Mol Biomed. 2020;1:7. Dec
Maciejowski J, Li Y, Bosco N, Campbell PJ, de Lange T. Chromothripsis and kataegis induced by telomere crisis. Cell. 2015;163:1641–54.
Shoshani O, Brunner SF, Yaeger R, Ly P, Nechemia-Arbely Y, Kim DH, et al. Chromothripsis drives the evolution of gene amplification in cancer. Nature. 2021;591:137–41.
Ly P, Teitz LS, Kim DH, Shoshani O, Skaletsky H, Fachinetti D, et al. Selective Y centromere inactivation triggers chromosome shattering in micronuclei and repair by non-homologous end joining. Nat Cell Biol. 2017;19:68–75.
Gao D, Li T, Li XD, Chen X, Li QZ, Wight-Carter M, et al. Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases. Proc Natl Acad Sci USA. 2015;112. Available from: https://doi.org/10.1073/pnas.1516465112.
Ahn J, Ruiz P, Barber GN. Intrinsic self-DNA triggers inflammatory disease dependent on STING. J Immunol. 2014;193:4634–42.
Simpson SR, Hemphill WO, Hudson T, Perrino FW. TREX1 – Apex predator of cytosolic DNA metabolism. DNA Repair. 2020;94:102894.
Lim J, Rodriguez R, Williams K, Silva J, Gutierrez AG, Tyler P, et al. The exonuclease TREX1 constitutes an Innate Immune checkpoint limiting cGAS/STING-mediated antitumor immunity. Cancer Immunol Res. 2024;12:663–72.
Toufektchan E, Dananberg A, Striepen J, Hickling JH, Shim A, Chen Y, et al. Intratumoral TREX1 induction promotes immune evasion by limiting type I IFN. Cancer Immunol Res. 2024;12:673–86.
Stetson DB, Ko JS, Heidmann T, Medzhitov R. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell. 2008;134:587–98.
Maciejowski J, Chatzipli A, Dananberg A, Chu K, Toufektchan E, Klimczak LJ, et al. APOBEC3-dependent kataegis and TREX1-driven chromothripsis during telomere crisis. Nat Genet. 2020;52:884–90.
Mazur DJ, Perrino FW. Excision of 3′ Termini by the Trex1 and TREX2 3′→5′ Exonucleases. J Biol Chem. 2001;276:17022–9.
Mohr L, Toufektchan E, Von Morgen P, Chu K, Kapoor A, Maciejowski J. ER-directed TREX1 limits cGAS activation at micronuclei. Mol Cell. 2021;81:724–.e9.
Fang L, Ying S, Xu X, Wu D. TREX1 cytosolic DNA degradation correlates with autoimmune disease and cancer immunity. Clin Exp Immunol. 2023;211:193–207.
Lin YF, Hu Q, Mazzagatti A, Valle-Inclán JE, Maurais EG, Dahiya R, et al. Mitotic clustering of pulverized chromosomes from micronuclei. Nature. 2023;618:1041–8.
Trivedi P, Steele CD, Au FKC, Alexandrov LB, Cleveland DW. Mitotic tethering enables inheritance of shattered micronuclear chromosomes. Nature. 2023;618:1049–56.
Shimizu N, Shingaki K, Kaneko-Sasaguri Y, Hashizume T, Kanda T. When, where and how the bridge breaks: anaphase bridge breakage plays a crucial role in gene amplification and HSR generation. Exp Cell Res. 2005;302:233–43.
Ciullo M. Initiation of the breakage-fusion-bridge mechanism through common fragile site activation in human breast cancer cells: the model of PIP gene duplication from a break at FRA7I. Hum Mol Genet. 2002;11:2887–94.
Lo AW, Sabatier L, Fouladi B, Pottier G, Ricoul M, Mumane JP. DNA amplification by breakage/fusion/bridge cycles initiated by spontaneous telomere loss in a human cancer cell line. Neoplasia. 2002;4:531–8.
Steele CD, Abbasi A, Islam SMA, Bowes AL, Khandekar A, Haase K, et al. Signatures of copy number alterations in human cancer. Nature. 2022;606:984–91.
Yang B, Luo L, Luo W, Zhou Y, Yang C, Xiong T, et al. The genomic dynamics during progression of lung adenocarcinomas. J Hum Genet. 2017;62:783–8.
Lopez V, Barinova N, Onishi M, Pobiega S, Pringle JR, Dubrana K, et al. Cytokinesis breaks dicentric chromosomes preferentially at pericentromeric regions and telomere fusions. Genes Dev. 2015;29:322–36.
Umbreit NT, Zhang CZ, Lynch LD, Blaine LJ, Cheng AM, Tourdot R, et al. Mechanisms generating cancer genome complexity from a single cell division error. Science. 2020;368:eaba0712.
Bennink ML, Leuba SH, Leno GH, Zlatanova J, De Grooth BG, Greve J. Unfolding individual nucleosomes by stretching single chromatin fibers with optical tweezers. Nat Struct Biol. 2001;8:606–10.
Fonseca CL, Malaby HLH, Sepaniac LA, Martin W, Byers C, Czechanski A, et al. Mitotic chromosome alignment ensures mitotic fidelity by promoting interchromosomal compaction during anaphase. J Cell Biol. 2019;218:1148–63.
Li S, Banck M, Mujtaba S, Zhou MM, Sugrue MM, Walsh MJ. p53-induced growth arrest is regulated by the mitochondrial SirT3 deacetylase. PLoS ONE. 2010;5:e10486.
Narkar A, Johnson BA, Bharne P, Zhu J, Padmanaban V, Biswas D, et al. On the role of p53 in the cellular response to aneuploidy. Cell Rep. 2021;34:108892.
Pfau SJ, Silberman RE, Knouse KA, Amon A. Aneuploidy impairs hematopoietic stem cell fitness and is selected against in regenerating tissues in vivo. Genes Dev. 2016;30:1395–408.
Sablina AA, Ilyinskaya GV, Rubtsova SN, Agapova LS, Chumakov PM, Kopnin; BP. Activation of p53-mediated cell cycle checkpoint in response to micronuclei formation. J Cell Sci. 1998;111:977–84.
Engeland K. Cell cycle regulation: p53-p21-RB signaling. Cell Death Differ. 2022;29:946–60.
Chen J. The cell-cycle arrest and apoptotic functions of p53 in tumor initiation and progression. Cold Spring Harb Perspect Med. 2016;6:a026104.
Uetake Y, Sluder G. Prolonged prometaphase blocks daughter cell proliferation despite normal completion of mitosis. Curr Biol. 2010;20:1666–71.
Lambrus BG, Uetake Y, Clutario KM, Daggubati V, Snyder M, Sluder G, et al. p53 protects against genome instability following centriole duplication failure. J Cell Biol. 2015;210:63–77.
Lambrus BG, Daggubati V, Uetake Y, Scott PM, Clutario KM, Sluder G, et al. A USP28–53BP1–p53–p21 signaling axis arrests growth after centrosome loss or prolonged mitosis. J Cell Biol. 2016;214:143–53.
Meitinger F, Belal H, Davis RL, Martinez MB, Shiau AK, Oegema K, et al. Control of cell proliferation by memories of mitosis. Science. 2024;383:1441–8.
Davoli T, Xu AW, Mengwasser KE, Sack LM, Yoon JC, Park PJ, et al. Cumulative haploinsufficiency and triplosensitivity drive aneuploidy patterns and shape the cancer genome. Cell. 2013;155:948–62.
Islam A, Manjarrez-González JC, Song X, Gore T, Draviam VM. Search for chromosomal instability aiding variants reveal naturally occurring kinetochore gene variants that perturb chromosome segregation. iScience. 2024;27:109007.
Tsang MJ, Cheeseman IM. Alternative CDC20 translational isoforms tune mitotic arrest duration. Nature. 2023;617:154–61.
Choo ZN, Behr JM, Deshpande A, Hadi K, Yao X, Tian H, et al. Most large structural variants in cancer genomes can be detected without long reads. Nat Genet. 2023;55:2139–48.
Garg S. Towards routine chromosome-scale haplotype-resolved reconstruction in cancer genomics. Nat Commun. 2023;14:1358.
Hart M, Adams SD, Draviam VM. Multinucleation associated DNA damage blocks proliferation in p53-compromised cells. Commun Biol. 2021;4:451.
Villot R, Poirier A, Bakan I, Boulay K, Fernández E, Devillers R, et al. ZNF768 links oncogenic RAS to cellular senescence. Nat Commun. 2021;12:4841.
Di Nardo M, Pallotta MM, Musio A. The multifaceted roles of cohesin in cancer. J Exp Clin Cancer Res. 2022;41:96.
Pati D. Role of chromosomal cohesion and separation in aneuploidy and tumorigenesis. Cell Mol Life Sci. 2024;81:100.
Vitre BD, Cleveland DW. Centrosomes, chromosome instability (CIN) and aneuploidy. Curr Opin Cell Biol. 2012;24:809–15.
LoMastro GM, Holland AJ. The emerging link between centrosome aberrations and metastasis. Dev Cell. 2019;49:325–31.
Yoshizawa K, Yaguchi K, Uehara R. Uncoupling of DNA replication and centrosome duplication cycles is a primary cause of haploid instability in mammalian somatic cells. Front Cell Dev Biol. 2020;8:721.
Godinho SA, Picone R, Burute M, Dagher R, Su Y, Leung CT, et al. Oncogene-like induction of cellular invasion from centrosome amplification. Nature. 2014;510:167–71.
Ganem NJ, Godinho SA, Pellman D. A mechanism linking extra centrosomes to chromosomal instability. Nature. 2009;460:278–82.
Zhang Y, Foreman O, Wigle DA, Kosari F, Vasmatzis G, Salisbury JL, et al. USP44 regulates centrosome positioning to prevent aneuploidy and suppress tumorigenesis. J Clin Investig. 2012;122:4362–74.
Foijer F, Xie SZ, Simon JE, Bakker PL, Conte N, Davis SH, et al. Chromosome instability induced by Mps1 and p53 mutation generates aggressive lymphomas exhibiting aneuploidy-induced stress. Proc Natl Acad Sci USA. 2014;111:13427–32.
Iwanaga Y, Chi YH, Miyazato A, Sheleg S, Haller K, Peloponese JM, et al. Heterozygous deletion of mitotic arrest-deficient protein 1 (MAD1) increases the incidence of tumors in mice. Cancer Res. 2007;67:160–6.
Michel LS, Liberal V, Chatterjee A, Kirchwegger R, Pasche B, Gerald W, et al. MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells. Nature. 2001;409:355–9.
Dai W, Wang Q, Liu T, Swamy M, Fang Y, Xie S, et al. Slippage of mitotic arrest and enhanced tumor development in mice with BubR1 haploinsufficiency. Cancer Res. 2004;64:440–5.
Suijkerbuijk SJE, van Osch MHJ, Bos FL, Hanks S, Rahman N, Kops GJPL. Molecular causes for BUBR1 dysfunction in the human cancer predisposition syndrome mosaic variegated aneuploidy. Cancer Res. 2010;70:4891–900.
Hanks S, Coleman K, Reid S, Plaja A, Firth H, Fitzpatrick D, et al. Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nat Genet. 2004;36:1159–61.
Sotillo R, Hernando E, Díaz-Rodríguez E, Teruya-Feldstein J, Cordón-Cardo C, Lowe SW, et al. Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. Cancer Cell. 2007;11:9–23.
Sapkota H, Wasiak E, Daum JR, Gorbsky GJ. Multiple determinants and consequences of cohesion fatigue in mammalian cells. Mol Biol Cell. 2018;29:1811–24.
Rowald K, Mantovan M, Passos J, Buccitelli C, Mardin BR, Korbel JO, et al. Negative selection and chromosome instability induced by Mad2 overexpression delay breast cancer but facilitate oncogene-independent outgrowth. Cell Rep. 2016;15:2679–91.
Lok TM, Wang Y, Xu WK, Xie S, Ma HT, Poon RYC. Mitotic slippage is determined by p31comet and the weakening of the spindle-assembly checkpoint. Oncogene. 2020;39:2819–34.
Gao YF, Li T, Chang Y, Wang YB, Zhang WN, Li WH, et al. Cdk1-phosphorylated CUEDC2 promotes spindle checkpoint inactivation and chromosomal instability. Nat Cell Biol. 2011;13:924–33.
Fujiwara T, Bandi M, Nitta M, Ivanova EV, Bronson RT, Pellman D. Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature. 2005;437:1043–7.
Vittoria MA, Quinton RJ, Ganem NJ. Whole-genome doubling in tissues and tumors. Trends Genet. 2023;39:954–67.
Chen S, Stout JR, Dharmaiah S, Yde S, Calvi BR, Walczak CE. Transient endoreplication down-regulates the kinesin-14 HSET and contributes to genomic instability. Mol Biol Cell. 2016;27:2911–23.
Lau TY, Poon RYC. Whole-genome duplication and genome instability in cancer cells: double the trouble. Int J Mol Sci. 2023;24:3733.
Berndt B, Zänker KS, Dittmar T. Cell fusion is a potent inducer of aneuploidy and drug resistance in tumor cell/ normal cell hybrids. Crit Rev Oncol. 2013;18:97–113.
Böhly N, Schmidt AK, Zhang X, Slusarenko BO, Hennecke M, Kschischo M, et al. Increased replication origin firing links replication stress to whole chromosomal instability in human cancer. Cell Rep. 2022;41:111836.
Wilhelm T, Olziersky AM, Harry D, De Sousa F, Vassal H, Eskat A, et al. Mild replication stress causes chromosome mis-segregation via premature centriole disengagement. Nat Commun. 2019;10:3585.
Shaikh N, Mazzagatti A, De Angelis S, Johnson SC, Bakker B, Spierings DCJ, et al. Replication stress generates distinctive landscapes of DNA copy number alterations and chromosome scale losses. Genome Biol. 2022;23:223.
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The authors thank Michael Schwab and High Fidelity Science communications for critical reading of the manuscript. Work in the Elowe Lab is supporterd by grants for the Canadian Instutes of Health Research (PJT186170), the National Science and Engineering council of Canada (RGPIN-2024-04516) and the Fonds de Recherche Nature et technologie du Québec (343032).
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Devillers, R., dos Santos, A., Destombes, Q. et al. Recent insights into the causes and consequences of chromosome mis-segregation. Oncogene (2024). https://doi.org/10.1038/s41388-024-03163-5
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DOI: https://doi.org/10.1038/s41388-024-03163-5
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