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

Computer analysis of a conserved domain, BRCT, first described at the carboxyl ter‐minus of the breast cancer protein BRCA1, a p53 binding protein (53BP1), and the yeast cell cycle checkpoint protein RAD9 revealed a large super‐ family of domains that occur predominantly in proteins involved in cell cycle checkpoint functions responsive to DNA damage. The BRCT domain consists of ~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 ~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, deoxycy‐ tidyl 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‐ri‐ bose) 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‐re‐ sponsive 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 car boxyterminal BRCT domain of BRCA1 corresponds precisely to the recently identified minimal transcription activation domain of this protein, indicating one such function.— Bork, P., Hofmann, K., Bucher, P., Neuwald, A. F., Altschul, S. F., Koonin, E. V. A superfamily of conserved domains in DNA damage‐responsive cell cycle checkpoint proteins. FASEB J. 11, 68‐ 76 (1997)