A cell cycle-dependent BRCA1-UHRF1 cascade regulates DNA double-strand break repair pathway choice.
Nat Commun
; 7: 10201, 2016 Jan 05.
Article
em En
| MEDLINE
| ID: mdl-26727879
ABSTRACT
BRCA1 is an important mediator of the DNA damage response, which promotes homologous recombination (HR) and antagonizes 53BP1-dependent non-homologous end joining in S/G2 phase. But how this is achieved remains unclear. Here, we report that the E3 ubiquitin ligase UHRF1 (Ubiquitin-like, with PHD and RING finger domains 1) directly participates in the interplay between BRCA1 and 53BP1. Mechanistically, UHRF1 is recruited to DNA double-strand breaks (DSBs) by BRCA1 in S phase, which requires the BRCT domain of BRCA1 and phosphorylated Ser674 of UHRF1. Subsequently, UHRF1 mediates K63-linked polyubiquitination of RIF1, and results in its dissociation from 53BP1 and DSBs thereby facilitating HR initiation. Thus, UHRF1 is a key regulator of DSB repair choice, which is separate from its role in heterochromatin formation and epigenetic regulator.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteína BRCA1
/
Proteínas Estimuladoras de Ligação a CCAAT
/
Reparo do DNA
/
Quebras de DNA de Cadeia Dupla
Limite:
Humans
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article