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 terminus of the breast cancer protein BRCA1, a p53 binding pr otein (53BP1), and the yeast cell cycle checkpoint protein RAD9 reveal ed 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 similar to 95 amino acid residues and occ urs 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 similar to 40 nonorthologous proteins, namely, BRCA1, 53BP1, and RAD9; a protein family that consists of the fission yeast replication checkpoint prote in Rad4, the oncoprotein ECT2, the DNA repair protein XRCC1, and yeast DNA polymerase subunit DPB11; DNA binding enzymes such as terminal de oxynucleotidyltransferases, deoxycytidyl transferase involved in DNA r epair, and DNA-ligases III and IV; yeast multifunctional transcription factor RAP1; and several uncharacterized gene products. Another previ ously described domain that is shared by bacterial NAD-dependent DNA-l igases, the large subunits of eukaryotic replication factor C, and pol y(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. D espite the functional diversity of all these proteins, participation i n DNA damage-responsive checkpoints appears to be a unifying theme. Th us, the BRCT domain is likely to perform critical, yet uncharacterized , functions in the cell cycle control of organisms from bacteria to hu mans. The carboxyterminal BRCT domain of BRCA1 corresponds precisely t o the recently identified minimal transcription activation domain of t his protein, indicating one such, function.