Neuronal enhancers are hotspots for DNA single-strand break repair
Defects in DNA repair frequently lead to neurodevelopmental and neurodegenerative diseases, underscoring the particular importance of DNA repair in long-lived post-mitotic neurons 1 , 2 . The cellular genome is subjected to a constant barrage of endogenous DNA damage, but surprisingly little is know...
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| Vydané v: | Nature (London) Ročník 593; číslo 7859; s. 440 - 444 |
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| Hlavní autori: | , , , , , , , , , , , , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | English |
| Vydavateľské údaje: |
London
Nature Publishing Group UK
20.05.2021
Nature Publishing Group |
| Predmet: | |
| ISSN: | 0028-0836, 1476-4687, 1476-4687 |
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| Shrnutí: | Defects in DNA repair frequently lead to neurodevelopmental and neurodegenerative diseases, underscoring the particular importance of DNA repair in long-lived post-mitotic neurons
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. 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.
DNA single-strand breaks in neurons accumulate at high levelsin functional enhancers. |
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| Bibliografia: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Author contributions W.W., S.E.H., W.J.N., J.P., K.W.C., M.E.W. and A.N. conceived, designed and analysed the experiments; W.W. designed bioinformatics pipelines, performed data analysis and designed the figures; S.E.H., E.C. and M.P. prepared i3Neurons for experiments; S.E.H. and E.C. performed gene knockdown, i3Neuron treatments, dissociation and collections in i3Neurons; J.P. and D.W. performed SAR-seq; W.J.N., J.P. and D.W. performed ChIP-seq; W.J.N. and N.V.W. performed S1 END-seq. S.E.H., E.C. and W.J.N. performed immunofluorescence imaging; A.C. developed SAR-seq in the A.N. laboratory; W.J.N. developed S1 END-seq; S.E.H. and M.E.W. selected guides for gene knockdown; K.S. performed ATAC-seq, did cloning for knock-down experiments and qRT–PCR; D.W. performed SEAL experiments; J.C.-M. prepared iMuscle cells; R.D.P. prepared primary rat neurons; S.E.H. treated and collected iMuscle and primary rat neurons; H.-Y.S. and S.C. conducted sequencing experiments in i3Neurons that were informative to the study; R.P. made MCF10A cells with Cas9-nickase; D.Z. and C.C. assisted with experiments; S.P. performed Hi-C, and S.K.J. and R.C. analysed the Hi-C data; H.H., P.J.M. and C.C. provided insights; K.W.C., M.E.W. and A.N. wrote the paper with input from all co-authors; M.E.W. and A.N. supervised the study. |
| ISSN: | 0028-0836 1476-4687 1476-4687 |
| DOI: | 10.1038/s41586-021-03468-5 |