Dissecting the role of p53 phosphorylation in homologous recombination provides new clues for gain-of-function mutants.
Nucleic Acids Res
; 36(16): 5362-75, 2008 Sep.
Article
en En
| MEDLINE
| ID: mdl-18697815
Regulation of homologous recombination (HR) represents the best-characterized DNA repair function of p53. The role of p53 phosphorylation in DNA repair is largely unknown. Here, we show that wild-type p53 repressed repair of DNA double-strand breaks (DSBs) by HR in a manner partially requiring the ATM/ATR phosphorylation site, serine 15. Cdk-mediated phosphorylation of serine 315 was dispensable for this anti-recombinogenic effect. However, without targeted cleavage of the HR substrate, serine 315 phosphorylation was necessary for the activation of topoisomerase I-dependent HR by p53. Moreover, overexpression of cyclin A1, which mimics the situation in tumors, inappropriately stimulated DSB-induced HR in the presence of oncogenic p53 mutants (not Wtp53). This effect required cyclin A1/cdk-mediated phosphorylation for stable complex formation with topoisomerase I. We conclude that p53 mutants have lost the balance between activation and repression of HR, which results in a net increase of potentially mutagenic DNA rearrangements. Our data provide new insight into the mechanism underlying gain-of-function of mutant p53 in genomic instability.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Recombinación Genética
/
Genes p53
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Proteína p53 Supresora de Tumor
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Reparación del ADN
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Mutación
Límite:
Humans
Idioma:
En
Revista:
Nucleic Acids Res
Año:
2008
Tipo del documento:
Article
País de afiliación:
Alemania
Pais de publicación:
Reino Unido