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...

The recurrent t(12;22) (q13;q12) chromosomal translocation associated with soft tissue clear cell sarcoma results in a chimeric protein EWS-ATF-1 that acts as a constitutive transcriptional activator. The CBP/p300 transcriptional coactivator, which links various transcriptional factors to basal transcription apparatus, participates in transcriptional activation, growth and cell cycle control and di erentiation. In this study, we show that EWS-ATF-1 associates constitutively with CBP both in vitro and in vivo. Both EWS and ATF-1 fusion domains are needed for this interaction. Here, we demonstrate that EWS-ATF-1 represses p53/CBP-mediated transactivation function. Overexpression of CBP can counteract this repressive e ect of EWS-ATF-1. Taken together, these ®ndings suggest that one of the mechanisms by which EWS-ATF-1 may cause tumors is through targeting CBP/p300 resulting in the loss of function of p53. This novel mechanism may be responsible for the development of these and other related solid tumors. Oncogene (2001) 20, 6653 ± 6659.

No abstract

No abstract

Abstract. CREB binding protein (CBP) is a transcriptional cofactor with intrinsic histone acetyl transferase activity (HAT). We have observed that CBP interacts with BRCA2 and mediates post-translational glycosylation of BRCA2. The binding of CBP to the amino-terminal region of BRCA2 is necessary for the glycosylation at residue 272 of BRCA2. Digestion with peptide N-glycosidase F indicates that the glycosylation of BRCA2 is N-linked. It is possible that this novel CBP-mediated post-translational N-glycosylation activity alters the conformation of CBP-interacting proteins, leading to regulation of gene expression, cell growth and differentiation.