Mapping the physical and functional interactions between the tumor suppressors p53 and BRCA2.
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.
Rajagopalan
Sridharan
S
Centre for Protein Engineering and Laboratory of Molecular Biology, Medical Research Council Centre, Cambridge, CB2 0QH, UK.
Andreeva
Antonina
A
Rutherford
Trevor J
TJ
Fersht
Alan R
AR
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*
D024682:BRCA2 Protein; D016159:Tumor Suppressor Protein p53; D004247:DNA