The BRCA2 is a histone acetyltransferase

Abstract

Patients carrying mutations in BRCA1 or BRCA2 tumor suppressor genes have shown to have high risk in developing breast and ovarian cancers. Two potential functions of BRCA2 were proposed which includes role in the regulation of transcription and also in DNA repair. Forty-®ve-amino acid region encoded by exon 3 of BRCA2 was shown to have transcriptional activation function. Recent studies of the several enzymes involved in acetylation and deacetylation of histone residues have revealed a possible relationship between gene transcriptional activation and histone acetylation. Since BRCA2 appear to function as a transcriptional factor, we have tested for Histone acetyl transferase (HAT) activity of BRCA2. Here, we present evidence that BRCA2 has intrinsic HAT activity, which maps to the aminoterminal region of BRCA2. Our results demonstrate that BRCA2 proteins acetylate primarily H3 and H4 of free histones. These observations suggest that HAT activity of BRCA2 may play an important role in the regulation of transcription and tumor suppressor function.Keywords: BRCA2; histone acetyl transferase; proteinprotein interaction; tumor suppressor Alterations in BRCA1 and BRCA2 tumor suppressor genes have been shown to be involved in 90% of familial breast cancers (Newman et al., 1988;Miki et al., 1994;Easton et al., 1993;Wooster et al., 1994;Wooster and Stratton, 1995). Recent studies revealed that both BRCA1 and BRCA2 are involved in ovarian and prostate cancers. Interestingly, BRCA2 was found to be more associated with male breast cancer compared to BRCA1 (Wooster et al., 1994). Patients with BRCA2 mutations were also found to be at a higher risk with a variety of other cancers including carcinomas of pancreas, prostate and colon (Thorlacius et al., 1996;Phelan et al., 1996;Gudmundsson et al., 1995;Tonin et al., 1995). The BRCA2 gene is composed of 27 exons and encodes a protein of 3418 amino-acids with no signi®cant homology to any known protein Bork et al., 1996). BRCA2 and BRCA1 proteins have been shown to interact with Rad 51 which suggests that they play a role in DNA repair (Scully et al., 1997;Sharan et al., 1997;Zhang et al., 1998). BRCA1 was also shown to induce apoptosis suggesting that BRCA proteins may play a role in the regulation of apoptosis of cells Rao et al., 1996). It remains to be seen whether BRCA2 plays a similar role in apoptosis.Interestingly, both BRCA1 and BRCA2 gene products are regulated in a cell cycle-dependent manner and have a potential transactivation function (Rajan et al., 1996;' Vaughn et al., 1996;Chapman and Verma, 1996; Monteriro et al., 1996;Milner et al., 1997;Wang et al., 1997;Cui et al., 1998a). Recently, we have shown that BRCA1 proteins interact with transcriptional coactivator CBP suggesting that BRCA1 has a role in the regulation of transcription (Cui et al., 1998b). Exon 3 of BRCA2 was found to have weak homology with transcriptional factor c-jun and also shown to activate transcription in mammalian cells (Milner et al., 1997). These results suggest that BRCA2r has a role in...

BRCA1 gene in breast cancer

“…A role for BRCA1 in TCR is consistent with its ability to recruit transcriptional cofactors and regulate transcription (''Regulation of Transcription''). Interestingly, a histone acetyltransferase (HAT) enzymatic function was mapped to the N-terminus of BRCA2 (Siddique et al, 1998). Although the BRCA1 C-terminus can recruit histone deacetylases (Yarden and Brody, 1998), it is not clear whether BRCA1 can directly regulate histone acetylation.…”

Fli-1b is generated by usage of differential splicing and alternative promoter

“…Previously we have shown that human Fli-1 and its related erg-2, erg-3 proteins act as sequence-speci®c transcriptional activators Siddique et al, 1993;Rao et al, 1993;Prasad et al, 1994). Here, we tested whether Fli-1b which lacks the ®rst exon can also act as a transcriptional activator.…”

“…Molecular characterization of these Ewing family of tumors revealed fusion of the EWS gene on chromosome 22, with either Fli-1 or erg genes located on chromosomes 11 and 21 respectively. Previously Fli-1 and Erg genes have been cloned by us and others (Ben-David et al, 1991;Prasad et al, 1992;Reddy et al, 1987) and the functional analysis of these proteins revealed that these proteins code for sequence-speci®c transcriptional activators with two transactivation domains present at amino-and carboxy-termini (Siddique et al, 1993;Rao et al, 1993). We and others have shown that EWS-Fli-1 and EWS-erg proteins encode transcriptional activators Baily et al, 1994) and these aberrant proteins show altered DNA binding and transactivation properties compared to normal Fli-1 and erg proteins.…”

BRCA2 associates with acetyltransferase activity when bound to P/CAF

“…During the preparation of this manuscript, Siddique et al (1998) reported that the BRCA2 is itself a histone acetyltransferase. These authors described that this activity maps to an N-terminal region of BRCA2 Figure 3 BRCA2 amino-terminus binds HAT activity in a P/ CAF-dependent manner.…”