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Active DNA demethylation promotes cell fate specification and the DNA damage response

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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… Click to show full 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. Description Active DNA demethylation in neurons The DNA of neurons is continually damaged due to lifelong, high-level metabolic and transcriptional activity. Recent studies have also demonstrated extensive “programmed” DNA damage in differentiating postmitotic neurons. Wang et al. identified endogenous lesions as single-strand-break intermediates of thymine DNA glycosylase (TDG)–mediated removal of oxidized methylcytosines during active DNA demethylation (see the Perspective by López-Moyado and Rao). Interrupting active DNA demethylation using antineoplastic cytosine analogs triggered TDG-dependent neuronal cell death. This work suggests that the well-known neurotoxic side effects of certain chemotherapies, also called “chemobrain, ” could be linked to DNA repair processes intrinsic to normal neuronal differentiation. —DJ Active DNA demethylation contributes to enhancer activation, lineage specification, and neurotoxicity during chemotherapy.

Keywords: active dna; dna demethylation; dna; dna damage

Journal Title: Science
Year Published: 2022

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