Active DNA demethylation promotes cell fate specification and the DNA damage response-Reference-Cited by-同舟云学术

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

Published:2022-12-02 Issue:6623 Volume:378 Page:983-989
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Wang Dongpeng¹^ORCID,Wu Wei¹²^ORCID,Callen Elsa¹^ORCID,Pavani Raphael¹^ORCID,Zolnerowich Nicholas¹^ORCID,Kodali Srikanth³⁴^ORCID,Zong Dali¹,Wong Nancy¹^ORCID,Noriega Santiago¹,Nathan William J.¹^ORCID,Matos-Rodrigues Gabriel¹^ORCID,Chari Raj⁵^ORCID,Kruhlak Michael J.⁶,Livak Ferenc¹^ORCID,Ward Michael⁷^ORCID,Caldecott Keith⁸^ORCID,Di Stefano Bruno³⁴^ORCID,Nussenzweig André¹^ORCID

Affiliation:

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.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Reference57 articles.

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