BRCA2 associates with acetyltransferase activity when bound to P/CAF

Abstract

Predisposition to hereditary breast cancer has been attributed in part to inherited mutations in the BRCA2 gene. The large protein it encodes is still poorly characterized with respect to functions. We have previously shown that BRCA2 has transcriptional activation potential conferred by its amino-terminal third exon. Here, we show that BRCA2 interacts with a transcriptional co-activator protein, P/CAF, which possesses histone acetyltransferase activity. The interaction with P/CAF is demonstrated in vitro as well as in vivo and is shown to be mediated by residues 290 ± 453 of BRCA2. Consistent with the binding to an acetyltransferase, BRCA2 is shown to associate with acetyltransferase activity in nuclear extracts. Contrary to a recent report, we ®nd no evidence in support of an intrinsic HAT activity in BRCA2 amino-terminus. Our results further substantiate the notion that BRCA2 has transcriptional activation function and suggest that one mechanism by which BRCA2 regulates transcription may be through the recruitment of histone-modifying activity of the P/CAF co-activator.

Cloning and Sequencing Full Length of Canine Brca2 and Rad51 cDNA.

“…Such evolutionarily conserved regions are expected to be of functional importance. A region in the N-terminus that interacts with a transcriptional co-activator protein p300/CBP-associated factor (P/CAF) is highly conserved in the canine sequence [6,10]. In the middle region corresponding to exon 11, we confirmed the presence of BRC repeats that participate in the interaction between Brca2 and Rad51, as revealed in a human study [21].…”

Conserved domains in the chicken homologue of BRCA2

“…Interestingly, a stretch of sequence (aa 176 ± 212 in human BRCA2) located between the transcriptional regulation and P/CAF interacting domains is conserved (indicated by a single asterisk and a line in Figure 1b and c) while no known motif or data regarding the function of this region have been published. In contrast, the adjacent P/CAFinteracting domain (aa 290 ± 453 in human BRCA2) (Fuks et al, 1998) is only modestly conserved between human and chicken (17% identify).…”

DNA polymerase stalling, sister chromatid recombination and the BRCA genes

“…BRCA2 also interacts and colocalizes with Rad51 and BRCA1 Sharan et al, 1997). BRCA2 has been reported to interact with at least one chromatin remodeling protein (Fuks et al, 1998). In addition to a DSBR defect, BRCA1 mutant cells reveal defects in transcription-coupled repair of oxidative DNA damage and, in some cases, G2/M checkpoint defects (Gowen et al, 1998;Xu et al, 1999).…”