Defects in DNA repair frequently lead to neurodevelopmental and neurodegenerative diseases, underscoring the particular importance of DNA repair in long-lived post-mitotic neurons1,2. The cellular genome is subjected to a constant barrage of endogenous DNA damage, but surprisingly little is known about the identity of the lesion(s) that accumulate in neurons and whether they accrue throughout the genome or at specific loci. Here we show that post-mitotic neurons accumulate unexpectedly high levels of DNA single-strand breaks (SSBs) at specific sites within the genome. Genome-wide mapping reveals that SSBs are located within enhancers at or near CpG dinucleotides and sites of DNA demethylation. These SSBs are repaired by PARP1 and XRCC1-dependent mechanisms. Notably, deficiencies in XRCC1-dependent short-patch repair increase DNA repair synthesis at neuronal enhancers, whereas defects in long-patch repair reduce synthesis. The high levels of SSB repair in neuronal enhancers are therefore likely to be sustained by both short-patch and long-patch processes. These data provide the first evidence of site- and cell-type-specific SSB repair, revealing unexpected levels of localized and continuous DNA breakage in neurons. In addition, they suggest an explanation for the neurodegenerative phenotypes that occur in patients with defective SSB repair.

Department of Genome Dynamics Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Department of Oncology MRC Weatherall Institute of Molecular Medicine University of Oxford John Radcliffe Hospital Oxford UK

Eunice Kennedy Shriver National Institute of Child Health and Human Development Bethesda MD USA

Genome Damage and Stability Centre School of Life Sciences University of Sussex Brighton UK

Laboratory of Biochemistry and Molecular Biology National Cancer Institute NIH Bethesda MD USA

Laboratory of Genome Integrity National Cancer Institute NIH Bethesda MD USA

Lymphocyte Nuclear Biology National Institute of Arthritis and Musculoskeletal and Skin Diseases and National Cancer Institute NIH Bethesda MD USA

National Eye Institute NIH Bethesda MD USA

National Institute of Neurological Disorders and Stroke NIH Bethesda MD USA

NIH Regulome Project NIH Bethesda MD USA

The Hakubi Center for Advanced Research and Radiation Biology Center Graduate School of Biostudies Kyoto University Kyoto Japan

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Nat Rev Mol Cell Biol. 2021 May;22(5):304-305. doi: 10.1038/s41580-021-00367-5. PubMed

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Neuron. 2021 Jun 2;109(11):1766-1768. doi: 10.1016/j.neuron.2021.05.008. PubMed

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Cell Death Differ. 2021 Nov;28(11):3193-3195. doi: 10.1038/s41418-021-00863-3. PubMed

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XRCC1 protects transcription from toxic PARP1 activity during DNA base excision repair