CCAR2 functions downstream of the Shieldin complex to promote double-strand break end-joining.
Proc Natl Acad Sci U S A
; 119(49): e2214935119, 2022 12 06.
Article
em En
| MEDLINE
| ID: mdl-36442094
ABSTRACT
The 53BP1-RIF1 pathway restricts the resection of DNA double-strand breaks (DSBs) and promotes blunt end-ligation by non-homologous end joining (NHEJ) repair. The Shieldin complex is a downstream effector of the 53BP1-RIF1 pathway. Here, we identify a component of this pathway, CCAR2/DBC1, which is also required for restriction of DNA end-resection. CCAR2 co-immunoprecipitates with the Shieldin complex, and knockout of CCAR2 in a BRCA1-deficient cell line results in elevated DSB end-resection, RAD51 loading, and PARP inhibitor (PARPi) resistance. Knockout of CCAR2 is epistatic with knockout of other Shieldin proteins. The S1-like RNA-binding domain of CCAR2 is required for its interaction with the Shieldin complex and for suppression of DSB end-resection. CCAR2 functions downstream of the Shieldin complex, and CCAR2 knockout cells have delayed resolution of Shieldin complex foci. Forkhead-associated (FHA)-dependent targeting of CCAR2 to DSB sites re-sensitized BRCA1-/-SHLD2-/- cells to PARPi. Taken together, CCAR2 is a functional component of the 53BP1-RIF1 pathway, promotes the refill of resected DSBs, and suppresses homologous recombination.
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1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quebras de DNA de Cadeia Dupla
/
Inibidores de Poli(ADP-Ribose) Polimerases
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article