RHINO directs MMEJ to repair DNA breaks in mitosis.
Science
; 381(6658): 653-660, 2023 08 11.
Article
em En
| MEDLINE
| ID: mdl-37440612
ABSTRACT
Nonhomologous end-joining (NHEJ) and homologous recombination (HR) are the primary pathways for repairing DNA double-strand breaks (DSBs) during interphase, whereas microhomology-mediated end-joining (MMEJ) has been regarded as a backup mechanism. Through CRISPR-Cas9-based synthetic lethal screens in cancer cells, we identified subunits of the 9-1-1 complex (RAD9A-RAD1-HUS1) and its interacting partner, RHINO, as crucial MMEJ factors. We uncovered an unexpected function for RHINO in restricting MMEJ to mitosis. RHINO accumulates in M phase, undergoes Polo-like kinase 1 (PLK1) phosphorylation, and interacts with polymerase θ (Polθ), enabling its recruitment to DSBs for subsequent repair. Additionally, we provide evidence that MMEJ activity in mitosis repairs persistent DSBs that originate in S phase. Our findings offer insights into the synthetic lethal relationship between the genes POLQ and BRCA1 and BRAC2 and the synergistic effect of Polθ and poly(ADP-ribose) polymerase (PARP) inhibitors.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Ciclo Celular
/
Exonucleases
/
Quebras de DNA de Cadeia Dupla
/
Reparo do DNA por Junção de Extremidades
/
Mitose
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Science
Ano de publicação:
2023
Tipo de documento:
Article