PARylated PDHE1α generates acetyl-CoA for local chromatin acetylation and DNA damage repair.
Journal
Nature structural & molecular biology
ISSN: 1545-9985
Titre abrégé: Nat Struct Mol Biol
Pays: United States
ID NLM: 101186374
Informations de publication
Date de publication:
Nov 2023
Nov 2023
Historique:
received:
18
08
2022
accepted:
21
08
2023
medline:
15
11
2023
pubmed:
22
9
2023
entrez:
22
9
2023
Statut:
ppublish
Résumé
Chromatin relaxation is a prerequisite for the DNA repair machinery to access double-strand breaks (DSBs). Local histones around the DSBs then undergo prompt changes in acetylation status, but how the large demands of acetyl-CoA are met is unclear. Here, we report that pyruvate dehydrogenase 1α (PDHE1α) catalyzes pyruvate metabolism to rapidly provide acetyl-CoA in response to DNA damage. We show that PDHE1α is quickly recruited to chromatin in a polyADP-ribosylation-dependent manner, which drives acetyl-CoA generation to support local chromatin acetylation around DSBs. This process increases the formation of relaxed chromatin to facilitate repair-factor loading, genome stability and cancer cell resistance to DNA-damaging treatments in vitro and in vivo. Indeed, we demonstrate that blocking polyADP-ribosylation-based PDHE1α chromatin recruitment attenuates chromatin relaxation and DSB repair efficiency, resulting in genome instability and restored radiosensitivity. These findings support a mechanism in which chromatin-associated PDHE1α locally generates acetyl-CoA to remodel the chromatin environment adjacent to DSBs and promote their repair.
Identifiants
pubmed: 37735618
doi: 10.1038/s41594-023-01107-3
pii: 10.1038/s41594-023-01107-3
doi:
Substances chimiques
Chromatin
0
Acetyl Coenzyme A
72-89-9
Pyruvates
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1719-1734Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.
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