Abstract
Telomere dysfunctions, rendered through replicative attrition of telomeric DNA or due to the removal of shelterin components, are recognized as DNA double-stranded breaks (DSBs) by the DNA damage repair (DDR) pathway. This leads to the activation of DNA damage checkpoint sensors, including the Mre11-Rad50-Nbs1 (MRN) complex, γ-H2AX and 53BP1, the ATM and ATR signal-transducing kinases, and downstream effectors, including Chk1, Chk2, and p53. Robust DNA damage response signals at dysfunctional telomeres, achieved by the complete deletion of TRF2 or by expressing dominant-negative mutant TPP1ΔRD, can be detected by their association with γ-H2AX and 53BP1 forming “telomere dysfunction induced foci (TIFs).” Induction of TIFs at telomeres provides an opportunity to quantify the extent of telomere dysfunction and monitor downstream signaling pathways.
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References
Palm W, de Lange T (2008) How shelterin protects mammalian telomeres. Annu Rev Genet 42:301–334
de Lange T (2009) How telomeres solve the end-protection problem. Science 326:948–952
de Lange T (2005) Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 19:2100–2110
Deng Y, Guo X, Ferguson DO et al (2009) Multiple roles for MRE11 at uncapped telomeres. Nature 460:914–918
Rai R, Zheng H, He H et al (2010) The function of classical and alternative non-homologous end-joining pathways in the fusion of dysfunctional telomeres. EMBO J 29:2598–2610
Rai R, Chen Y, Lei M, Chang S (2016) TRF2-RAP1 is required to protect telomeres from engaging in homologous recombination-mediated deletions and fusions. Nat Commun 7:10881. doi:10.1038/ncomms10881
d’Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, Saretzki G, Carter NP, Jackson SP (2003) A DNA damage checkpoint response in telomere initiated senescence. Nature 426:194–198
Takai H, Smogorzewska A, de Lange T (2003) DNA damage foci at dysfunctional telomeres. Curr Biol 13:1549–1556
Liu D, Safari A, O’Connor MS et al (2004) PTOP interacts with POT1 and regulates its localization to telomeres. Nat Cell Biol 6:673–680
Guo X, Deng Y, Lin Y et al (2007) Dysfunctional telomeres activate an ATM-ATR-dependent DNA damage response to suppress tumorigenesis. EMBO J 26:4709–4719
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Rai, R., Chang, S. (2017). Probing the Telomere Damage Response. In: Songyang, Z. (eds) Telomeres and Telomerase. Methods in Molecular Biology, vol 1587. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-6892-3_13
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DOI: https://doi.org/10.1007/978-1-4939-6892-3_13
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Publisher Name: Humana Press, New York, NY
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Online ISBN: 978-1-4939-6892-3
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