Active DNA demethylation promotes cell fate specification and the DNA damage response
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.
| Errataetall: |
CommentIn: Science. 2022 Dec 2;378(6623):948-949. - PMID 36454845 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:378 |
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| Enthalten in: |
Science (New York, N.Y.) - 378(2022), 6623 vom: 02. Dez., Seite 983-989 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wang, Dongpeng [VerfasserIn] |
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| Links: |
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| Themen: |
5-Methylcytosine |
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| Anmerkungen: |
Date Completed 06.12.2022 Date Revised 19.09.2023 published: Print-Electronic CommentIn: Science. 2022 Dec 2;378(6623):948-949. - PMID 36454845 Citation Status MEDLINE |
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| doi: |
10.1126/science.add9838 |
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| Förderinstitution / Projekttitel: |
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| 520 | |a 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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| 700 | 1 | |a Pavani, Raphael |e verfasserin |4 aut | |
| 700 | 1 | |a Zolnerowich, Nicholas |e verfasserin |4 aut | |
| 700 | 1 | |a Kodali, Srikanth |e verfasserin |4 aut | |
| 700 | 1 | |a Zong, Dali |e verfasserin |4 aut | |
| 700 | 1 | |a Wong, Nancy |e verfasserin |4 aut | |
| 700 | 1 | |a Noriega, Santiago |e verfasserin |4 aut | |
| 700 | 1 | |a Nathan, William J |e verfasserin |4 aut | |
| 700 | 1 | |a Matos-Rodrigues, Gabriel |e verfasserin |4 aut | |
| 700 | 1 | |a Chari, Raj |e verfasserin |4 aut | |
| 700 | 1 | |a Kruhlak, Michael J |e verfasserin |4 aut | |
| 700 | 1 | |a Livak, Ferenc |e verfasserin |4 aut | |
| 700 | 1 | |a Ward, Michael |e verfasserin |4 aut | |
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| 700 | 1 | |a Di Stefano, Bruno |e verfasserin |4 aut | |
| 700 | 1 | |a Nussenzweig, André |e verfasserin |4 aut | |
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