From BRCA1 to RAP1: a widespread BRCT module closely associated with DNA repair

Abstract

Inherited mutations in BRCA1 predispose to breast and ovarian cancer, but the biological function of the BRCA1 protein has remained largely elusive. The recent correspondence of Koonin et al. [Koonin, E.V., Altschul, S.F. and Bork, P. (1996) Nature Genet. 13, 266-267] has emphasized the potential importance of the BRCA1 C-terminal region for BRCA1-mediated breast cancer suppression, as this domain shows similarities with the C-terminal regions of a p53-binding protein (53BP1), the yeast RAD9 protein involved in DNA repair, and two uncharacterized, hypothetical proteins (KIAA0170 and SPAC19G10.7). The highlighted domain has been suggested to be the result of an internal duplication, each of the tandem domains being designated as a 'BRCT domain' (for BRCA1 C-terminus). Sequence analysis using hydrophobic cluster analysis reveals here the presence of 50 copies of the BRCT domain in 23 different proteins, including, in addition to BRCA1, 53BP1 and RAD9, XRCC1, RAD4, Ect2, REV1, Crb2, RAP1, terminal deoxynucleotidyltransferases (TdT) and three eukaryotic DNA ligases. Most of these proteins are known to be involved in DNA repair. The BRCT domain is not limited to the C-termini of protein sequences and can be found in multiple copies or in a single copy as in RAP1 and TdT, suggesting that it could well constitute an autonomous folding unit of approx. 90-100 amino acids.