Neuronal enhancers are hotspots for DNA single-strand break repair

Wei Wu, Sarah E. Kargbo-Hill, William J. Nathan, Jacob Paiano, Elsa Callen, Dongpeng Wang, Kenta Shinoda, Niek Wietmarschen, Jennifer M. Colón-Mercado, Dali Zong, Raffaella Pace, Han-Yu Shih, Steve Coon, Maia Parsadanian, Raphael Pavani, Hana Hanzlikova, Solji Park, Seol Kyoung Jung, Peter J. McHugh, Andres Canela, Chongyi Chen, Rafael Casellas, Keith W. Caldecott (), Michael E. Ward () and André Nussenzweig ()
Additional contact information
Wei Wu: National Cancer Institute, NIH
Sarah E. Kargbo-Hill: National Institute of Neurological Disorders and Stroke, NIH
William J. Nathan: National Cancer Institute, NIH
Jacob Paiano: National Cancer Institute, NIH
Elsa Callen: National Cancer Institute, NIH
Dongpeng Wang: National Cancer Institute, NIH
Kenta Shinoda: National Cancer Institute, NIH
Niek Wietmarschen: National Cancer Institute, NIH
Jennifer M. Colón-Mercado: National Institute of Neurological Disorders and Stroke, NIH
Dali Zong: National Cancer Institute, NIH
Raffaella Pace: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Han-Yu Shih: National Eye Institute, NIH
Steve Coon: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Maia Parsadanian: National Institute of Neurological Disorders and Stroke, NIH
Raphael Pavani: National Cancer Institute, NIH
Hana Hanzlikova: Institute of Molecular Genetics of the Czech Academy of Sciences
Solji Park: National Institute of Arthritis and Musculoskeletal and Skin Diseases and National Cancer Institute, NIH
Seol Kyoung Jung: National Institute of Arthritis and Musculoskeletal and Skin Diseases and National Cancer Institute, NIH
Peter J. McHugh: University of Oxford, John Radcliffe Hospital
Andres Canela: Kyoto University
Chongyi Chen: National Cancer Institute, NIH
Rafael Casellas: National Institute of Arthritis and Musculoskeletal and Skin Diseases and National Cancer Institute, NIH
Keith W. Caldecott: Institute of Molecular Genetics of the Czech Academy of Sciences
Michael E. Ward: National Institute of Neurological Disorders and Stroke, NIH
André Nussenzweig: National Cancer Institute, NIH

Nature, 2021, vol. 593, issue 7859, 440-444

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41586-021-03468-5

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