Neuronal enhancers are hotspots for DNA single-strand break repair.
Neuronal enhancers are hotspots for DNA single-strand break repair.
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DOI：
10.1038/s41586-021-03468-5
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发表时间：
2021-05
期刊：
影响因子：
64.8
通讯作者：
中科院分区：
文献类型：
--
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DNA修复缺陷经常导致神经发育和神经退行性疾病，强调了DNA修复在长寿命有丝分裂后神经元中的特殊重要性。细胞基因组不断受到内源性DNA损伤的影响，但令人惊讶的是，人们对积累在神经元中的损伤(S)的身份以及它们是在整个基因组中还是在特定的基因位点上积累的知之甚少。在这里，我们展示了有丝分裂后的神经元在基因组中的特定位置积累了出人意料的高水平的DNA单链断裂(SSB)。全基因组图谱显示，SSB位于CpG二核苷酸或其附近的增强子和DNA去甲基化部位。这些SSB通过PARP1和XRCC1依赖的机制修复。值得注意的是，依赖XRCC1的短补丁修复的缺陷增加了神经元增强剂的DNA修复合成，而长补丁修复的缺陷减少了合成。因此，神经元增强剂中高水平的SSB修复很可能被短补丁和长补丁过程所维持。这些数据提供了位置和细胞类型特异性SSB修复的第一个证据，揭示了神经元中意想不到的局部和持续的DNA断裂水平。此外，他们还对SSB修复缺陷患者出现的神经退行性变表型提出了解释。
Defects in DNA repair frequently lead to neurodevelopmental and neurodegenerative diseases, underscoring the particular importance of DNA repair in long-lived post-mitotic neurons. 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.
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影响因子：
14.9
作者：
Hanzlikova H;Gittens W;Krejcikova K;Zeng Z;Caldecott KW
通讯作者：
Caldecott KW
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通讯作者：
Hubbard TJ
影响因子：
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通讯作者：
Smith, Hamilton O.
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