PALB2 is an integral component of the BRCA complex required for homologous recombination repair.
Mutations in breast cancer susceptibility gene 1 and 2 (BRCA1 and BRCA2) predispose individuals to breast and ovarian cancer development. We previously reported an in vivo interaction between BRCA1 and BRCA2. However, the biological significance of their association is thus far undefined. Here, we report that PALB2, the partner and localizer of BRCA2, binds directly to BRCA1, and serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2 complex. The association between BRCA1 and PALB2 is primarily mediated via apolar bonding between their respective coiled-coil domains. More importantly, BRCA1 mutations identified in cancer patients disrupted the specific interaction between BRCA1 and PALB2. Consistent with the converging functions of the BRCA proteins in DNA repair, cells harboring mutations with abrogated BRCA1-PALB2 interaction resulted in defective homologous recombination (HR) repair. We propose that, via its direct interaction with PALB2, BRCA1 fine-tunes recombinational repair partly through its modulatory role in the PALB2-dependent loading of BRCA2-RAD51 repair machinery at DNA breaks. Our findings uncover PALB2 as the molecular adaptor between the BRCA proteins, and suggest that impaired HR repair is one of the fundamental causes for genomic instability and tumorigenesis observed in patients carrying BRCA1, BRCA2, or PALB2 mutations.
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Shirley M H
SM
Sy
Michael S Y
MS
Huen
Junjie
J
Chen
D000595:Amino Acid Sequence; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D053960:DNA Breaks; D004260:DNA Repair / Q000235:genetics*; D000076164:Fanconi Anemia Complementation Group N Protein; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D019313:BRCA1 Protein; D024682:BRCA2 Protein; D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins; D004247:DNA