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 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 修复缺陷经常导致神经发育和神经退行性疾病，强调了 DNA 修复在长寿命的有丝分裂后神经元中的特殊重要性^1,2. 细胞基因组不断遭受内源性 DNA 损伤，但令人惊讶的是，人们对神经元中累积的损伤的特性以及它们是在整个基因组中还是在特定位点累积，知之甚少。在这里，我们表明有丝分裂后神经元在基因组内的特定位点积累了意想不到的高水平 DNA 单链断裂 (SSB)。全基因组图谱显示 SSB 位于增强子内或靠近 CpG 二核苷酸和 DNA 去甲基化位点。这些 SSB 由 PARP1 和 XRCC1 依赖机制修复。值得注意的是，依赖于 XRCC1 的短补丁修复缺陷会增加神经元增强子的 DNA 修复合成，而长补丁修复缺陷会减少合成。因此，神经元增强子中的高水平 SSB 修复可能由短补丁和长补丁过程维持。这些数据提供了位点和细胞类型特异性 SSB 修复的第一个证据，揭示了神经元中意外水平的局部和连续 DNA 断裂。此外，他们提出了对 SSB 修复缺陷患者出现的神经退行性表型的解释。