title: Dissecting the role of p53 phosphorylation in homologous recombination provides new clues for gain-of-function mutants.
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.
authors.affiliation: Department of Obstetrics and Gynecology, University of Ulm, 89075 Ulm, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Restle
authors.forename: Martin
authors.initials: M
authors.lastname: Färber
authors.forename: Cindy
authors.initials: C
authors.lastname: Baumann
authors.forename: Michael
authors.initials: M
authors.lastname: Böhringer
authors.forename: Karl Heinz
authors.initials: KH
authors.lastname: Scheidtmann
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
authors.forename: Lisa
authors.initials: L
authors.lastname: Wiesmüller
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors; D019925:Cyclin A / Q000378:metabolism; D056750:Cyclin A1; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D015252:Deoxyribonucleases, Type II Site-Specific / Q000378:metabolism; D016158:Genes, p53; D006801:Humans; D020014:K562 Cells; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011995:Recombination, Genetic; D029701:Saccharomyces cerevisiae Proteins; D012694:Serine / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors
chemical_list: C503745:CCNA1 protein, human; D018797:Cell Cycle Proteins; D019925:Cyclin A; D056750:Cyclin A1; D004268:DNA-Binding Proteins; D029701:Saccharomyces cerevisiae Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D012694:Serine; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; C037725:SCEI protein, S cerevisiae; D015252:Deoxyribonucleases, Type II Site-Specific; D004264:DNA Topoisomerases, Type I