Widespread chromatin context-dependencies of DNA double-strand break repair proteins.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
22 Jun 2024
22 Jun 2024
Historique:
received:
19
02
2024
accepted:
28
05
2024
medline:
23
6
2024
pubmed:
23
6
2024
entrez:
22
6
2024
Statut:
epublish
Résumé
DNA double-strand breaks are repaired by multiple pathways, including non-homologous end-joining (NHEJ) and microhomology-mediated end-joining (MMEJ). The balance of these pathways is dependent on the local chromatin context, but the underlying mechanisms are poorly understood. By combining knockout screening with a dual MMEJ:NHEJ reporter inserted in 19 different chromatin environments, we identified dozens of DNA repair proteins that modulate pathway balance dependent on the local chromatin state. Proteins that favor NHEJ mostly synergize with euchromatin, while proteins that favor MMEJ generally synergize with distinct types of heterochromatin. Examples of the former are BRCA2 and POLL, and of the latter the FANC complex and ATM. Moreover, in a diversity of human cancer types, loss of several of these proteins alters the distribution of pathway-specific mutations between heterochromatin and euchromatin. Together, these results uncover a complex network of proteins that regulate MMEJ:NHEJ balance in a chromatin context-dependent manner.
Identifiants
pubmed: 38909016
doi: 10.1038/s41467-024-49232-x
pii: 10.1038/s41467-024-49232-x
doi:
Substances chimiques
Chromatin
0
Heterochromatin
0
Euchromatin
0
BRCA2 Protein
0
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
5334Subventions
Organisme : ZonMw (Netherlands Organisation for Health Research and Development)
ID : 91215067
Organisme : EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)
ID : 694466
Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)
ID : U54DK107965
Informations de copyright
© 2024. The Author(s).
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