Language

English

Publication Date

12-2-2022

Journal

Science

DOI

10.1126/science.add9838

PMID

36454826

PMCID

PMC10196940

PubMedCentral® Posted Date

6-2-2023

PubMedCentral® Full Text Version

Author MSS

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.

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

Published Open-Access

yes

Download

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.