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. Breast cancer and ovarian cancer is estimated to be responsible for more than one-fifth of cancer mortality (1). Because germ-line mutations in breast cancer susceptibility gene 1 and 2 (BRCA1 and BRCA2) account for the development of a significant portion of hereditary breast and ovarian cancer, the understanding of their roles in tumor suppression is crucial to the improvement of therapeutic interventions. Because accumulation of genetic aberrations are often observed in cells derived from familial breast cancer patients with BRCA1 or BRCA2 mutations, the BRCA proteins have been considered as the caretakers of genomic integrity. Accordingly, tumor cells derived from these patients exhibit hypersensitivity to DNA damaging agents and display genomic instability (2-4).Given the similar phenotypes in BRCA1 and BRCA2 patients, and the spectrum of deficits observed in cells deficient in these proteins, one would envision that the BRCA proteins might work in synchrony in certain cellular process(es) essential for tumor suppression. Consistent with this notion, interaction between the 2 BRCA proteins has been reported (5). However, exactly how their interaction is regulated and the biological significance for such interaction remains largely unexplored.BRCA1 participates in numerous cellular processes (3, 6-8). In particular, BRCA1 has been proposed to have diverse roles to promote cell survival in response to genotoxic stress. Recent elucidation of multiple BRCA1 complexes in vivo suggests a multifactorial model by which BRCA1 mediates distinct processes that include checkpoint activation, damage signaling, and DNA repair (9, 10). However, BRCA2 has a pivotal r...

The breast and ovarian cancer type 1 susceptibility protein (BRCA1) has pivotal roles in the maintenance of genome stability. Studies support that BRCA1 exerts its tumour suppression function primarily through its involvement in cell cycle checkpoint control and DNA damage repair. In addition, recent proteomic and genetic studies have revealed the presence of distinct BRCA1 complexes in vivo, each of which governs a specific cellular response to DNA damage. Thus, BRCA1 is emerging as the master regulator of the genome through its ability to execute and coordinate various aspects of the DNA damage response.

Homologous recombination mediated by the RAD51 recombinase helps eliminate chromosomal lesions, such as DNA double-stranded breaks induced by radiation or arising from injured DNA replication forks. The tumor suppressors BRCA2 and PALB2 act together to deliver RAD51 to chromosomal lesions to initiate repair. Here we document a new function of PALB2 in the enhancement of RAD51's ability to form the D-loop. We show that PALB2 binds DNA and physically interacts with RAD51. Importantly, while PALB2 alone stimulates D-loop formation, a co-operative effect is seen with RAD51AP1, an enhancer of RAD51. This stimulation stems from PALB2's ability to function with RAD51 and RAD51AP1 to assemble the synaptic complex. Our results help unveil a multi-faceted role of PALB2 in chromosome damage repair. Since PALB2 mutations can cause breast and other tumors or lead to Fanconi anemia, our findings are important for understanding the mechanism of tumor suppression in humans.