Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle Proteins / antagonists & inhibitors
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Cyclin A / metabolism
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Cyclin A1
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Cyclin-Dependent Kinase 2 / metabolism
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Cyclin-Dependent Kinases / metabolism
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DNA Breaks, Double-Stranded
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DNA Repair*
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DNA Topoisomerases, Type I / metabolism
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DNA-Binding Proteins / antagonists & inhibitors
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Deoxyribonucleases, Type II Site-Specific / metabolism
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Genes, p53*
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Humans
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K562 Cells
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Mutation*
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Phosphorylation
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Recombination, Genetic*
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Saccharomyces cerevisiae Proteins
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Serine / metabolism
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Tumor Suppressor Protein p53 / chemistry
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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Tumor Suppressor Proteins / antagonists & inhibitors
Substances
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CCNA1 protein, human
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Cell Cycle Proteins
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Cyclin A
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Cyclin A1
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DNA-Binding Proteins
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Saccharomyces cerevisiae Proteins
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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Serine
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ATM protein, human
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ATR protein, human
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Ataxia Telangiectasia Mutated Proteins
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Protein Serine-Threonine Kinases
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinases
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SCEI protein, S cerevisiae
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Deoxyribonucleases, Type II Site-Specific
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DNA Topoisomerases, Type I