Roles of BRCA2 and PALB2 in homology-directed repair of chromosomal breaks

Germline mutations in the tumor suppressors BRCA2 and PALB2 predispose carriers to early-onset breast and ovarian cancers and the cancer-prone syndrome Fanconi anemia. BRCA2- and PALB2-deficient cells exhibit chromosomal instability and increased sensitivity to genotoxic agents. The involvement of BRCA2 and PALB2 genes in DNA double-strand break repair through the error-free homologous recombination (HR) pathway is likely to account for these phenotypic changes. The studies presented in this work are aimed at defining the mechanistic roles of BRCA2 and PALB2 during the process of HR. Chapter 2 describes the biochemical characterization of BRCA2 DNA-binding domain that harbors a significant portion of cancer-derived missense mutations. Chapter 3 presents the functional analysis of PALB2 and the molecular dissection of its amino-terminal region. By deciphering the precise roles of BRCA2 and PALB2 in HR we may be able to understand how mutations in these genes lead to tumorigenesis.