Dissecting the role of p53 phosphorylation in homologous recombination provides new clues for gain-of-function mutants.

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.
Mesh Terms:
Ataxia Telangiectasia Mutated Proteins, Cell Cycle Proteins, Cyclin A, Cyclin A1, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinases, DNA Breaks, Double-Stranded, DNA Repair, DNA Topoisomerases, Type I, DNA-Binding Proteins, Deoxyribonucleases, Type II Site-Specific, Genes, p53, Humans, K562 Cells, Mutation, Phosphorylation, Protein-Serine-Threonine Kinases, Recombination, Genetic, Saccharomyces cerevisiae Proteins, Serine, Tumor Suppressor Protein p53, Tumor Suppressor Proteins
Nucleic Acids Res. Sep. 01, 2008; 36(16);5362-75 [PUBMED:18697815]
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