Active DNA demethylation promotes cell fate specification and the DNA damage response.
Science
; 378(6623): 983-989, 2022 12 02.
Article
de 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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Éléments activateurs (génétique)
/
Thymine DNA glycosylase
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Réparation de l'ADN
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Cassures simple-brin de l'ADN
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Cellules souches pluripotentes induites
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Déméthylation de l'ADN
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Neurones
Limites:
Humans
Langue:
En
Journal:
Science
Année:
2022
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique