研究人员使用两种有丝分裂后的谱系特化系统（诱导多能干细胞衍生的神经元和转分化的巨噬细胞），表明胸苷DNA糖基化酶（TDG）驱动ten-eleven易位酶（TET）氧化的甲基胞嘧啶切除是单链DNA断裂（SSB）的一个来源。尽管巨噬细胞的分化倾向于用短片碱基切除修复来填补单核苷酸缺口，但神经元也经常使用长片亚途径。
使用抗肿瘤的胞嘧啶类似物破坏这种缺口填补过程，会引发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去甲基化促进了内源性DNA损伤，这一过程通常能保障细胞的特性，但也能在抗癌治疗后引发神经毒性。
据介绍，神经元拥有高水平的SSB，其靶标是神经元增强子，但这种内源性损伤的来源仍不清楚。
附：英文原文
Title: Active DNA demethylation promotes cell fate specification and the DNA damage response
Author: Dongpeng Wang, Wei Wu, Elsa Callen, Raphael Pavani, Nicholas Zolnerowich, Srikanth Kodali, Dali Zong, Nancy Wong, Santiago Noriega, William J. Nathan, Gabriel Matos-Rodrigues, Raj Chari, Michael J. Kruhlak, Ferenc Livak, Michael Ward, Keith Caldecott, Bruno Di Stefano, André Nussenzweig
Issue&Volume: 2022-12-02
Abstract: 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.
DOI: add9838
Source: https://www.science.org/doi/10.1126/science.add9838