2025/05/01 by Francisco Neal, Wenjing Li, Mollie E. Uhrig +16 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #CRISPR and Genetic Engineering #DNA Repair Mechanisms #PARP inhibition in cancer therapy
paper · pdf · doi:10.1016/j.celrep.2025.115654
openalex publication_date 2025/05/01 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
Homologous recombination (HR) removes DNA double-strand breaks (DSBs) and preserves stressed DNA replication forks. Successful HR execution requires the tumor suppressor BRCA2, which harbors distinct DNA-binding domains (DBDs): one that possesses three oligonucleotide/oligosaccharide-binding (OB) folds (OB-DBD) and another residing in the C-terminal recombinase binding domain (CTRB-DBD). Here, we employ multi-faceted approaches to delineate the contributions of these domains toward HR and replication fork maintenance. We show that OB-DBD and CTRB-DBD confer single-strand DNA (ssDNA)- and dsDNA-binding capabilities, respectively, and that BRCA2 variants mutated in either domain are impaired in their ability to load the recombinase RAD51 onto ssDNA pre-occupied by RPA. While the CTRB-DBD mutant is modestly affected by DNA break repair, it exhibits a strong defect in the protection of stressed replication forks. In contrast, the OB-DBD is indispensable for both BRCA2 functions. Our study thus defines the unique contributions of the two BRCA2 DBDs in genome maintenance.