Breast and ovarian cancer is estimated to be responsible for 20% of cancer mortality among woman. Familial breast cancer can result from impaired genome stability control following mutations in homologous recombinational repair proteins such as BRCA2. BRCA2 plays a pivotal role in controlling the function and localization of RAD51. The BRC repeats located at the center of BRCA2 confer a very complicated mode of regulation. The BRC repeats bind RAD51 and control RAD51 nucleoprotein filament formation in conjunction with the BRCA2 DNA-binding domain, whereas another, BRC-unrelated RAD51-binding motif at the C-terminus of BRCA2 appears to stabilize the filament. Importantly, point mutations in BRC repeats are found in individuals predisposed to breast cancer (http://research.nhgri.nih.gov/bic/http://research.nhgri.nih.gov).

 

It is now believed that BRCA2 and PALB2 are two important regulators of the RAD51 recombinase. PALB2 was identified as a major partner of BRCA2 and shown to be an essential upstream regulator of BRCA2 intranuclear localization and its HR function. PALB2 depletion compromised DNA repair and cell survival in response to genotoxic stress. Furthermore, multiple independent studies have established PALB2 as the central core of a BRCA1-PALB2-BRCA2 complex essential for HR. Although PALB2 affects homologous recombination, mechanistic and structural insights as well as  how PALB2 promotes tumorigenesis are still poorly understood. Moreover, no therapeutical therapy has been established against PALB2-dependent cancers. These issues are assessed in details in our lab.