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Distinct roles of the two BRCA2 DNA-binding domains in DNA damage repair and replication fork preservation
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DOI：10.1016/j.celrep.2025.115654.png)
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Abstract
En 中文
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 dsDNAbinding 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.
Keywords:
HOMOLOGOUS RECOMBINATION
BRCA2-DEFICIENT CELLS
END RESECTION
HUMAN RAD51
MECHANISM
DELETION
REPEATS
HYPERSENSITIVITY
DIFFUSION
DEFECTS
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