Active DNA Demethylation Promotes Cell Fate Specification and the DNA Damage Response

Authors

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

Publication Date

12-2-2022

Journal

Science

DOI

10.1126/science.add9838

PMID

PMC10196940

PMCID

PMC10196940

PubMedCentral® Posted Date

6-2-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Cell Differentiation, DNA Demethylation, Induced Pluripotent Stem Cells, Neurons, DNA Breaks, Single-Stranded, Enhancer Elements, Genetic, Thymine DNA Glycosylase, DNA Repair, 5-Methylcytosine, Humans, Cell Transdifferentiation

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.

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