DNA binding and RAD51 engagement by the BRCA2 C-terminus orchestrate DNA repair and replication fork preservation

Youngho Kwon, Heike Rösner, Weixing Zhao, Platon Selemenakis, Zhuoling He, Ajinkya S. Kawale, Jeffrey N. Katz, Cody M. Rogers, Francisco E. Neal, Aida Badamchi Shabestari, Valdemaras Petrosius, Akhilesh K. Singh, Marina Z. Joel, Lucy Lu, Stephen P. Holloway, Sandeep Burma, Bipasha Mukherjee, Robert Hromas, Alexander Mazin, Claudia Wiese (), Claus S. Sørensen () and Patrick Sung ()
Additional contact information
Youngho Kwon: University of Texas Health Science Center at San Antonio
Heike Rösner: University of Copenhagen
Weixing Zhao: University of Texas Health Science Center at San Antonio
Platon Selemenakis: Colorado State University
Zhuoling He: University of Texas Health Science Center at San Antonio
Ajinkya S. Kawale: University of Texas Health Science Center at San Antonio
Jeffrey N. Katz: University of Texas Health Science Center at San Antonio
Cody M. Rogers: University of Texas Health Science Center at San Antonio
Francisco E. Neal: University of Texas Health Science Center at San Antonio
Aida Badamchi Shabestari: University of Texas Health Science Center at San Antonio
Valdemaras Petrosius: University of Copenhagen
Akhilesh K. Singh: Yale University School of Medicine
Marina Z. Joel: Yale University School of Medicine
Lucy Lu: Yale University School of Medicine
Stephen P. Holloway: University of Texas Health Science Center at San Antonio
Sandeep Burma: University of Texas Health Science Center at San Antonio
Bipasha Mukherjee: University of Texas Health Science Center at San Antonio
Robert Hromas: University of Texas Health at San Antonio
Alexander Mazin: University of Texas Health Science Center at San Antonio
Claudia Wiese: Colorado State University
Claus S. Sørensen: University of Copenhagen
Patrick Sung: University of Texas Health Science Center at San Antonio

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-36211-x

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