Abstract
The neuronal genome is particularly sensitive to loss or attenuation of DNA repair, and many neurological diseases ensue when DNA repair is impaired. It is well-established that the neuronal genome is subjected to stochastic DNA damage, most likely because of extensive oxidative stress in the brain. However, recent studies have identified unexpected high levels of ‘programmed’ DNA breakage in neurons, which we propose arise during physiological DNA metabolic processes intrinsic to neuronal development, differentiation and maintenance. The role of programmed DNA breaks in normal neuronal physiology and disease remains relatively unexplored thus far. However, bulk and single-cell sequencing analyses of neurodegenerative diseases have revealed age-related somatic mutational signatures that are enriched in regulatory regions of the genome. Here, we explore a paradigm of DNA repair in neurons, in which the genome is safeguarded from erroneous impacts of programmed genome breakage intrinsic to normal neuronal function.
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Acknowledgements
K.W.C. is supported by Programme Grants from the UK Medical Research Council (grant no. MR/P010121/1), Cancer Research UK (grant no. C6563/A7322) and by ERC Advanced Investigator (SIDSCA grant no. 694996) and Royal Society Wolfson Research Merit Awards. The M.E.W. laboratory is supported by the NINDS Intramural Research Program. The A.N. laboratory is supported by the Intramural Research Program of the NIH, an Ellison Medical Foundation Senior Scholar in Aging Award (grant no. AG-SS-2633-11), the Department of Defense Awards (grant nos. W81XWH-16-1-599 and W81XWH-19-1-0652), the Alex’s Lemonade Stand Foundation Award and an NIH Intramural FLEX Award.
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Caldecott, K.W., Ward, M.E. & Nussenzweig, A. The threat of programmed DNA damage to neuronal genome integrity and plasticity. Nat Genet 54, 115–120 (2022). https://doi.org/10.1038/s41588-021-01001-y
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DOI: https://doi.org/10.1038/s41588-021-01001-y
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