The PCNA-associated protein PARI negatively regulates homologous recombination via the inhibition of DNA repair synthesis.
Nucleic Acids Res
; 44(7): 3176-89, 2016 Apr 20.
Article
em En
| MEDLINE
| ID: mdl-26792895
ABSTRACT
Successful and accurate completion of the replication of damage-containing DNA requires mainly recombination and RAD18-dependent DNA damage tolerance pathways. RAD18 governs at least two distinct mechanisms translesion synthesis (TLS) and template switching (TS)-dependent pathways. Whereas TS is mainly error-free, TLS can work in an error-prone manner and, as such, the regulation of these pathways requires tight control to prevent DNA errors and potentially oncogenic transformation and tumorigenesis. In humans, the PCNA-associated recombination inhibitor (PARI) protein has recently been shown to inhibit homologous recombination (HR) events. Here, we describe a biochemical mechanism in which PARI functions as an HR regulator after replication fork stalling and during double-strand break repair. In our reconstituted biochemical system, we show that PARI inhibits DNA repair synthesis during recombination events in a PCNA interaction-dependent way but independently of its UvrD-like helicase domain. In accordance, we demonstrate that PARI inhibits HR in vivo, and its knockdown suppresses the UV sensitivity of RAD18-depleted cells. Our data reveal a novel human regulatory mechanism that limits the extent of HR and represents a new potential target for anticancer therapy.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Ligação a DNA
/
Reparo de DNA por Recombinação
Tipo de estudo:
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
Nucleic Acids Res
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
República Tcheca