A superfamily of conserved domains in DNA damage‐ responsive cell cycle checkpoint proteins

Abstract

Computer analysis of a conserved domain, BRCT, first described at the carboxyl terminus of the breast cancer protein BRCA1, a p53 binding protein (53BP1), and the yeast cell cycle checkpoint protein RAD9 revealed a large superfamily of domains that occur predominantly in proteins involved in cell cycle checkpoint functions responsive to DNA damage. The BRCT domain consists of approximately 95 amino acid residues and occurs as a tandem repeat at the carboxyl terminus of numerous proteins, but has been observed also as a tandem repeat at the amino terminus or as a single copy. The BRCT superfamily presently includes approximately 40 nonorthologous proteins, namely, BRCA1, 53BP1, and RAD9; a protein family that consists of the fission yeast replication checkpoint protein Rad4, the oncoprotein ECT2, the DNA repair protein XRCC1, and yeast DNA polymerase subunit DPB11; DNA binding enzymes such as terminal deoxynucleotidyltransferases, deoxycytidyl transferase involved in DNA repair, and DNA-ligases III and IV; yeast multifunctional transcription factor RAP1; and several uncharacterized gene products. Another previously described domain that is shared by bacterial NAD-dependent DNA-ligases, the large subunits of eukaryotic replication factor C, and poly(ADP-ribose) polymerases appears to be a distinct version of the BRCT domain. The retinoblastoma protein (a universal tumor suppressor) and related proteins may contain a distant relative of the BRCT domain. Despite the functional diversity of all these proteins, participation in DNA damage-responsive checkpoints appears to be a unifying theme. Thus, the BRCT domain is likely to perform critical, yet uncharacterized, functions in the cell cycle control of organisms from bacteria to humans. The carboxyterminal BRCT domain of BRCA1 corresponds precisely to the recently identified minimal transcription activation domain of this protein, indicating one such function.

A targeted disruption of the murine Brca1 gene causes γ-irradiation hypersensitivity and genetic instability

“…Instead of BRC motifs, a conserved C-terminal domain of human and mouse BRCA1 proteins (BRCT) is also found in many nonorthologous proteins including 53BP1, RAD9, XRCC1 and others. Proteins with BRCT domain comprise a superfamily, and all of them appear involved in DNA damage responsive checkpoints (Bork et al, 1997). In addition to a BRCT domain, a ring zinc ®nger found at the N-terminal of human and mouse BRCA1 suggests it has the ability to bind to DNA (Bienstock et al, 1996) or another protein (Mackay and Crossley, 1998).…”

BRCA1 gene in breast cancer

“…Deletion of a short segment or cancer-associated point mutations in the minimal TAD led to ablation of activity. A third clue to BRCA1 function is that computer analysis suggests that the minimal TAD contains a tandem repeat of about 95 aa (called ''BRCT'' for BRCA1 Cterminus) similar to C-terminal domains found in a variety of proteins involved in cell cycle checkpoints and DNA repair (Koonin et al, 1996;Bork et al, 1997;Williams et al, 2001). As described below, the BRCT domain of BRCA1 mediates protein interactions that are critical to its role in transcriptional regulation and the response to DNA damage.…”

Phosphorylation of the cytokinesis regulator ECT2 at G2/M phase stimulates association of the mitotic kinase Plk1 and accumulation of GTP-bound RhoA

“…The carboxy-terminal (C-terminal) half of ECT2 contains a tandem array of the Dbl-homology (DH) and pleckstrin-homology (PH) domains, which catalyse guanine nucleotide exchange on Rho GTPases (Tatsumoto et al, 1999;Saito et al, 2004). The amino-terminal (N-terminal) half of ECT2 contains the tandem BRCA1-C terminal (BRCT) repeats, which associate with proteins involved in DNA repair and cell cycle checkpoint response (Bork et al, 1997;Callebaut and Mornon, 1997). ECT2 is localized in the nucleus of interphase cells.…”