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


Wang Dongpeng1ORCID,Wu Wei12ORCID,Callen Elsa1ORCID,Pavani Raphael1ORCID,Zolnerowich Nicholas1ORCID,Kodali Srikanth34ORCID,Zong Dali1,Wong Nancy1ORCID,Noriega Santiago1,Nathan William J.1ORCID,Matos-Rodrigues Gabriel1ORCID,Chari Raj5ORCID,Kruhlak Michael J.6,Livak Ferenc1ORCID,Ward Michael7ORCID,Caldecott Keith8ORCID,Di Stefano Bruno34ORCID,Nussenzweig André1ORCID


1. Laboratory of Genome Integrity, National Cancer Institute NIH, Bethesda, MD, USA.

2. State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.

3. Stem Cells and Regenerative Medicine, Center for Cell and Gene Therapy, Department of Molecular and Cellular Biology and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.

4. Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

5. Genome Modification Core, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.

6. Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.

7. National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.

8. Genome Damage and Stability Centre, University of Sussex, Falmer Brighton, UK.


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.


American Association for the Advancement of Science (AAAS)



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