title: Distinct binding of BRCA2 BRC repeats to RAD51 generates differential DNA damage sensitivity.
abstract: BRCA2 is a multi-faceted protein critical for the proper regulation of homology-directed repair of DNA double-strand breaks. Elucidating the mechanistic features of BRCA2 is crucial for understanding homologous recombination and how patient-derived mutations impact future cancer risk. Eight centrally located BRC repeats in BRCA2 mediate binding and regulation of RAD51 on resected DNA substrates. Herein, we dissect the biochemical and cellular features of the BRC repeats tethered to the DNA binding domain of BRCA2. To understand how the BRC repeats and isolated domains of BRCA2 contribute to RAD51 binding, we analyzed both the biochemical and cellular properties of these proteins. In contrast to the individual BRC repeat units, we find that the BRC5-8 region potentiates RAD51-mediated DNA strand pairing and provides complementation functions exceeding those of BRC repeats 1-4. Furthermore, BRC5-8 can efficiently repair nuclease-induced DNA double-strand breaks and accelerate the assembly of RAD51 repair complexes upon DNA damage. These findings highlight the importance of the BRC5-8 domain in stabilizing the RAD51 filament and promoting homology-directed repair under conditions of cellular DNA damage.
authors.affiliation: Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Gouri
authors.initials: G
authors.lastname: Chatterjee
authors.affiliation: Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Judit
authors.initials: J
authors.lastname: Jimenez-Sainz
authors.affiliation: Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Presti
authors.affiliation: Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA ryan.jensen@yale.edu.
authors.forename: Ryan B
authors.initials: RB
authors.lastname: Jensen
mesh_terms: D020816:Amino Acid Motifs; D024682:BRCA2 Protein / Q000737:chemistry / Q000378:metabolism*; D004249:DNA Damage; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D051135:Rad51 Recombinase / Q000378:metabolism*
chemical_list: D024682:BRCA2 Protein; D051135:Rad51 Recombinase