Insights into the molecular basis of human hereditary breast cancer from studies of the BRCA1 BRCT domain.
The C-terminal, BRCT repeats of BRCA1 are essential for the tumor suppressor function of this protein. Here we review structural and functional studies of this domain. Both repeats adopt similar folds and pack in an intimate, head-to-tail manner. The domain binds phosphorylated targets such as the DNA damage-associated kinase BACH1, with a specificity for pSer-X-X-Phe motifs. Structural studies reveal that the N-terminal repeat is responsible for pSer binding while a groove at the interface of the two repeats recognizes the Phe. Missense variants identified in breast cancer screening programs often disrupt these interactions and these molecular defects may lead to an increased cancer risk.
Glover
J N Mark
JN
Department of Biochemistry, University of Alberta, T6G 2H7, Edmonton, AB, Canada. mark.glover@ualberta.ca
D019313:BRCA1 Protein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics*; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008967:Molecular Biology; D020125:Mutation, Missense; D009386:Neoplastic Syndromes, Hereditary / Q000175:diagnosis / Q000235:genetics; D012680:Sensitivity and Specificity
D019313:BRCA1 Protein; D004273:DNA, Neoplasm; D047908:Intracellular Signaling Peptides and Proteins