title: Mapping the physical and functional interactions between the tumor suppressors p53 and BRCA2.
abstract: p53 maintains genome integrity either by regulating the transcription of genes involved in cell cycle, apoptosis, and DNA repair or by interacting with partner proteins. Here we provide evidence for a direct physical interaction between the tumor suppressors p53 and BRCA2. We found that the transactivation domain of p53 made specific interactions with the C-terminal oligonucleotide/oligosaccharide-binding-fold domains of BRCA2 (BRCA2(CTD)). A second distinct site situated on the p53 DNA-binding domain, bound to a region containing BRC repeats of BRCA2 (BRCA2([BRC1-8])) and may contribute synergistically for high affinity association of intact full-length proteins. Overexpression of BRCA2 and BRCA2(CTD) suppressed the transcriptional activity of p53 with a concomitant reduction in the expression of p53-target genes such as Bax and p21. Consequently, p53-mediated apoptosis was significantly attenuated by BRCA2. The observed physical association of p53 and BRCA2 may have important functional implications in the p53 transactivation-independent suppression of homologous recombination and suggests a possible interregulatory role for both proteins in apoptosis and DNA repair.
authors.affiliation: Centre for Protein Engineering and Laboratory of Molecular Biology, Medical Research Council Centre, Cambridge, CB2 0QH, UK.
authors.forename: Sridharan
authors.initials: S
authors.lastname: Rajagopalan
authors.forename: Antonina
authors.initials: A
authors.lastname: Andreeva
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Rutherford
authors.forename: Alan R
authors.initials: AR
authors.lastname: Fersht
mesh_terms: D017209:Apoptosis; D024682:BRCA2 Protein / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D011485:Protein Binding; D025941:Protein Interaction Mapping; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D020539:Sequence Analysis, Protein; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D024682:BRCA2 Protein; D016159:Tumor Suppressor Protein p53; D004247:DNA