biostudies-literatureKwon YUnited States Department of Defense | United States Army | Army Medical Command | Congressionally Directed Medical Research ProgramsNIA NIH HHSNIEHS NIH HHSAmerican Chemical SocietyKræftens BekæmpelseNCI NIH HHSLundbeck FoundationU.S. Department of Health & Human Services | National Institutes of HealthCancer Prevention and Research Institute of TexasNIGMS NIH HHS432https://www.ebi.ac.uk/biostudies/studies/S-EPMC9879961biostudies-literatureUnknown14(1)The tumor suppressor BRCA2 participates in DNA double-strand break repair by RAD51-dependent homologous recombination and protects stressed DNA replication forks from nucleolytic attack. We demonstrate that the C-terminal Recombinase Binding (CTRB) region of BRCA2, encoded by gene exon 27, harbors a DNA binding activity. CTRB alone stimulates the DNA strand exchange activity of RAD51 and permits the utilization of RPA-coated ssDNA by RAD51 for strand exchange. Moreover, CTRB functionally synergizes with the Oligonucleotide Binding fold containing DNA binding domain and BRC4 repeat of BRCA2 in RPA-RAD51 exchange on ssDNA. Importantly, we show that the DNA binding and RAD51 interaction attributes of the CTRB are crucial for homologous recombination and protection of replication forks against MRE11-mediated attrition. Our findings shed light on the role of the CTRB region in genome repair, reveal remarkable functional plasticity of BRCA2, and help explain why deletion of Brca2 exon 27 impacts upon embryonic lethality.Nature communicationsDNA binding and RAD51 engagement by the BRCA2 C-terminus orchestrate DNA repair and replication fork preservation.PMC9879961R01 GM136717R01 GM141091RO1 CA168635RR180029R01 CA246807PO1 CA92584R01 ES007061F30CA260908R35 CA241801RO1 ES007061R56 ES021454P01 CA092584R223-2016-8R01 CA268641BC191160R01 CA188347RP170345R01 CA237286R01 CA168635F30 CA260908R50 CA265315R01 CA205224T32 AG021890T32CA148724R01CA246807T32 CA148724RR210023R01 CA23728PF-22-034-01-DMCR167-A10921-B224RP220269Badamchi Shabestari ARosner HMazin ASelemenakis PZhao WMukherjee BSorensen CSRogers CMHolloway SPSung PPetrosius VSingh AKLu LKawale ASHe ZNeal FEJoel MZKwon YWiese CKatz JNBurma SHromas RfalseDNA binding and RAD51 engagement by the BRCA2 C-terminus orchestrate DNA repair and replication fork preservation.The tumor suppressor BRCA2 participates in DNA double-strand break repair by RAD51-dependent homologous recombination and protects stressed DNA replication forks from nucleolytic attack. We demonstrate that the C-terminal Recombinase Binding (CTRB) region of BRCA2, encoded by gene exon 27, harbors a DNA binding activity. CTRB alone stimulates the DNA strand exchange activity of RAD51 and permits the utilization of RPA-coated ssDNA by RAD51 for strand exchange. Moreover, CTRB functionally synergizes with the Oligonucleotide Binding fold containing DNA binding domain and BRC4 repeat of BRCA2 in RPA-RAD51 exchange on ssDNA. Importantly, we show that the DNA binding and RAD51 interaction attributes of the CTRB are crucial for homologous recombination and protection of replication forks against MRE11-mediated attrition. Our findings shed light on the role of the CTRB region in genome repair, reveal remarkable functional plasticity of BRCA2, and help explain why deletion of Brca2 exon 27 impacts upon embryonic lethality.2023-01-01T00:00:00Z2023 Jan2026-03-17T15:44:57.675Z2025-04-04T20:34:47.866ZS-EPMC98799613670290210.1038/s41467-023-36211-x