Correspondence to: RA Eeles pattern during spermatogenesis also suggests that these genes can function beyond DNA replication, since brca1 and brca2 transcripts expressed for longer periods than the PCNA protein. Brca1, brca2 and rad51 nullizygous mice all show early embryonic lethality, associated with a proliferation deficit (Gowen et al, 1996; Ludwig et al, 1997; Suzuki et al, 1997) and it is very interesting to note that coincident homozygous p53 mutation can partially suppress this lethality (Ludwig et al, 1997). The cells of BRCA1-and BRCA2-deficient tumours are often aneuploid (Marcus et al, 1996) and cells of brca2 mutant mice have aberrant chromosome structure coupled with inefficient DNA repair (Patel et al, 1998), which suggests that both genes are involved in the maintenance of genomic stability. Consistent with this hypothesis, brca2 nullizygous embryos exhibit X-ray hypersensitivity (Sharan et al, 1997). It has been shown that the human pancreatic adenocarcinoma cell line Capan-1, which has only one copy of the BRCA2 gene with a mutation producing a truncated protein eliminating the RAD51 interacting domain, has a striking deficiency in double-strand break repair (Abbott et al, 1998). These studies clearly demonstrate a role for BRCA1 and BRCA2 in DNA break repair and in the maintenance of genome integrity. Looking into the protein structures of these gene products very little is revealed about the possible function. The BRCA1 protein has a RING finger in its N terminal globular region, which could be involved in DNA binding (Thakur et al, 1997). The tandem BRCT domain at the C terminal region (aa 1560–1863) has transcriptional activation function, as it transactivates gene expression when fused to a heterologous DNA binding domain (Monteiro et al, 1996). Furthermore, this BRCT motif is a relatively common feature of proteins involved in DNA repair or cell cycle checkpoint function (Bork et al, 1997; Calebaut et al, 1997). It has also been demonstrated that BRCA1 is physically associated with the RNA polymerase II complex (Scully et al, 1997) through RNA helicase A that interacts with the carboxy terminus of BRCA1 and links it to the complex (Anderson et al, 1998). Recent studies implicate that BRCA1 acts as a transcriptional co-activator and increases the TP53-dependent transcription from P21 and BAX promoters (Zhang et al, 1998). The interaction between BRCA1 and TP53 has been mapped to aa 224–500 of BRCA1 and the C terminal domain of TP53. These results would indicate that BRCA1 and TP53 may coordinately regulate gene expression; however, BRCA1 has also been found to transactivate the expression of P21, the major cyclin-dependent kinase inhibitor, in a TP53-independent manner (Somasundaram et al, 1997). These data suggest BRCA1 involvement in the inhibition of cell cycle progression into the S phase.

BRCA2 also has transcription activating function, which was localized to a highly conserved region at the amino acid terminus. Regions in exon 3 of BRCA2 show sequence homology with CJUN and this exon has the potential to activate transcription in yeast (Milner et al, 1997). The BRCA2 protein has been shown to have histone acetyl-transferase (HAT) activity (Siddique et al, 1998), although this study was criticized, claiming that BRCA2 does not have intrinsic HAT activity but interacts with P/CAF1, a histone acetyltransferase (Fuks et al, 1998). Either way both studies suggest that BRCA2 participates in transcriptional regulation, as disrupting the nucleosomal structure through acetylation of certain histones is a possible mechanism for transcriptional activation. Transcriptional response to …