Neurons harbor high levels of single-strand DNA breaks (SSBs) that are targeted to neuronal enhancers, but the source of this endogenous damage remains unclear. Using two systems of postmitotic lineage specification—induced pluripotent stem cell–derived neurons and transdifferentiated macrophages—we show that thymidine DNA glycosylase (TDG)–driven excision of methylcytosines oxidized with ten-eleven translocation enzymes (TET) is a source of SSBs. Although macrophage differentiation favors short-patch base excision repair to fill in single-nucleotide gaps, neurons also frequently use the long-patch subpathway. Disrupting this gap-filling process using anti-neoplastic cytosine analogs triggers a DNA damage response and neuronal cell death, which is dependent on TDG. Thus, TET-mediated active DNA demethylation promotes endogenous DNA damage, a process that normally safeguards cell identity but can also provoke neurotoxicity after anticancer treatments.

中文翻译：

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主动 DNA 去甲基化促进细胞命运规范和 DNA 损伤反应

神经元具有高水平的单链 DNA 断裂 (SSB)，这些断裂是针对神经元增强子的，但这种内源性损伤的来源仍不清楚。使用有丝分裂后谱系规范的两个系统——诱导多能干细胞衍生的神经元和转分化的巨噬细胞——我们发现胸苷DNA糖基化酶（TDG）驱动的被10-11个易位酶（TET）氧化的甲基胞嘧啶的切除是SSB的来源。尽管巨噬细胞分化有利于短补丁碱基切除修复来填补单核苷酸间隙，但神经元也经常使用长补丁子通路。使用抗肿瘤胞嘧啶类似物破坏这种间隙填充过程会触发 DNA 损伤反应和神经元细胞死亡，这取决于 TDG。因此，TET 介导的主动 DNA 去甲基化会促进内源性 DNA 损伤，这一过程通常可以保护细胞身份，但也可能在抗癌治疗后引发神经毒性。