Major finding: BRCA1–BARD1 binds to RAD51 to enhance its activity in the promotion of homologous DNA pairing.
Clinical relevance: A cancer-associated BARD1 mutation prevents RAD51 binding to impair homologous recombination.
Impact: BRCA1–BARD1 mutations that block RAD51 binding may impair DSB repair and tumor suppressive functions.
Mutations in the BRCA1 tumor suppressor are associated with the development of breast and ovarian cancers and Fanconi anemia. BRCA1 forms a complex with BARD1 to facilitate DNA double-strand break (DSB) repair by homologous recombination, but the role of BRCA1 remains to be defined. During repair, the DSB ends are resected to yield 3′ single-stranded DNA tails that interact with RAD51 to form the presynaptic filament, which invades a homologous duplex target to form the displacement loop (D-loop) to initiate DSB repair. To investigate the mechanism by which BRCA1-BARD1 promotes homologous recombination, Zhao and colleagues developed a system to coexpress BRCA1 and BARD1 in insect cells to obtain protein complexes for biochemical assays. BRCA1–BARD1 bound preferentially to the D-loop or DNA bubble (unwound DNA that forms during processes including transcription), indicating that the BRCA1–BARD1 complex has a structure-specific DNA binding activity. BRCA1–BARD1 bound directly to RAD51 and enhanced its recombinase activity, promoting D-loop formation via an enhancement of synaptic complex assembly. Mutations in BRCA1 or BARD1 that disrupted the RAD51 interaction prevented DNA strand invasion and impaired homologous recombination. One such mutation in BARD1 (K140N) was found in two patients with cancer (colorectal adenocarcinoma and uterine corpus endometrial carcinoma) in the cBioPortal, and weakened RAD51 binding, D-loop formation, and synaptic complex assembly. These findings elucidate a mechanism by which BRCA1—BARD1 interacts with RAD51 to promote DNA strand invasion in homologous recombination, facilitating DSB repair. Further, mutations disrupting the BRCA1–BARD1 interaction with RAD51 may impair DSB repair by homologous recombination and disrupt the tumor suppressive role of BRCA1–BARD1.
Notes
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.
- ©2017 American Association for Cancer Research.
Volume 7, Issue 12
