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

Science. 2022 Dec 2;378(6623):983-989. doi: 10.1126/science.add9838. Epub 2022 Dec 1.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Thymine DNA Glycosylase
  • 5-Methylcytosine