Active DNA demethylation promotes cell fate specification and the DNA damage response.
Science
; 378(6623): 983-989, 2022 12 02.
Article
em En
| MEDLINE
| ID: mdl-36454826
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.
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Base de dados:
MEDLINE
Assunto principal:
Elementos Facilitadores Genéticos
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Timina DNA Glicosilase
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Reparo do DNA
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Quebras de DNA de Cadeia Simples
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Células-Tronco Pluripotentes Induzidas
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Desmetilação do DNA
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Neurônios
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article