Conserved domains in the chicken homologue of BRCA2

Abstract

Germline mutation of the BRCA2 gene causes a high risk of developing breast and ovarian cancer. Although the BRCA2 protein has been implicated in homologous recombination (HR) of DNA and in transcription, it is still unclear how mutation leads to tumorigenesis. We have identi®ed a nonmammalian homologue of BRCA2 from chicken, which encodes a protein with 3397 amino acids (aa) and shows only 40% identity to human BRCA2. However, comparison of the mammalian and chicken sequences revealed remarkably high homology in several segments. These include a Nterminal region (*100 aa), which was previously shown to possess intrinsic transcriptional activity, and a C-terminal region (aa residue *2480-*3180 in human BRCA2), which has not been clearly assigned any function. In contrast, although the eight BRC repeats of mammalian BRCA2 are believed to play an important role in HR by interacting with Rad51, the BRC3, BRC5, and BRC6 repeats exhibit virtually no similarity to their mammalian counterparts. Among 311 missense mutations listed as unclassi®ed variants in the NIH Breast Cancer Information Core database, only 83 of these sites are identical in chicken BRCA2. Thus, chicken BRCA2 may provide a means to identify domains and residues associated with cancer predisposition.

BRCA2: a universal recombinase regulator

“…Perhaps surprisingly, orthologues of the BRCA2 gene have been found in a variety of evolutionary diverse taxa (Figure 4a), such as the smut fungus Ustilago maydis (UmBRH2) (Kojic et al, 2002), the nematode Caenorhabditis elegans (CeBRC-2) (Martin et al, 2005), the plant Arabidopsis thaliana (AtBRCA2) (Siaud et al, 2004), as well as vertebrates such as chicken (cBRCA2) (Takata et al, 2002) (Figure 4a). Human BRCA2 is a very large polypeptide of 3418 amino acids and it contains a number of recognizable motifs, some of which can be found in all BRCA2 homologues.…”

Defects in homologous recombination repair behind the human diseases: FA and HBOC

“…In the middle part (the residues between 990 and 2100), BRCA2 harbors eight tandem BRC repeats, each consisting of about 30 amino acids, which are well conserved across human, mouse, rat and chicken (Takata et al 2002, Yang et al 2002. Not only the sequences themselves but also the spacing between them is well conserved across species.…”

“…Shahid and coworkers recently revealed the structure of full-length BRCA2 as being a dimer, using cryo-EM 3D reconstruction (Shahid et al 2014). The sequence conservation among BRCA2 orthologs among various species is mostly limited to the N-terminal, the middle part, and the C-terminal regions; therefore, these regions may be more important for genome maintenance (Takata et al 2002).…”

The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability

“…BRCA2 binds directly to RAD51 through its C-terminus and the BRC repeats located in the middle of the protein. These repeats are highly conserved across species, while most of the intervening sequences are not, suggesting that the BRC repeats are important for BRCA2 function (Bignell et al, 1997;Takata et al, 2002;Warren et al, 2002). Of the eight BRC repeats in the BRCA2 protein, RAD51 has been shown to bind to BRC1-4, BRC7 and BRC8, which are the more highly conserved repeats (Bignell et al, 1997;Wong et al, 1997).…”