Structural insights into BCDX2 complex function in homologous recombination

Yashpal Rawal, Lijia Jia, Aviv Meir, Shuo Zhou, Hardeep Kaur, Eliza A. Ruben, Youngho Kwon, Kara A. Bernstein, Maria Jasin, Alexander B. Taylor, Sandeep Burma, Robert Hromas, Alexander V. Mazin, Weixing Zhao, Daohong Zhou, Elizabeth V. Wasmuth, Eric C. Greene (), Patrick Sung () and Shaun K. Olsen ()
Additional contact information
Yashpal Rawal: University of Texas Health Science Center at San Antonio
Lijia Jia: University of Texas Health Science Center at San Antonio
Aviv Meir: Columbia University Irving Medical Center
Shuo Zhou: University of Texas Health Science Center at San Antonio
Hardeep Kaur: University of Texas Health Science Center at San Antonio
Eliza A. Ruben: University of Texas Health Science Center at San Antonio
Youngho Kwon: University of Texas Health Science Center at San Antonio
Kara A. Bernstein: University of Pennsylvania School of Medicine
Maria Jasin: Developmental Biology Program, Memorial Sloan Kettering Cancer Center
Alexander B. Taylor: University of Texas Health Science Center at San Antonio
Sandeep Burma: University of Texas Health Science Center at San Antonio
Robert Hromas: University of Texas Health Science Center at San Antonio
Alexander V. Mazin: University of Texas Health Science Center at San Antonio
Weixing Zhao: University of Texas Health Science Center at San Antonio
Daohong Zhou: University of Texas Health Science Center at San Antonio
Elizabeth V. Wasmuth: University of Texas Health Science Center at San Antonio
Eric C. Greene: Columbia University Irving Medical Center
Patrick Sung: University of Texas Health Science Center at San Antonio
Shaun K. Olsen: University of Texas Health Science Center at San Antonio

Nature, 2023, vol. 619, issue 7970, 640-649

Abstract: Abstract Homologous recombination (HR) fulfils a pivotal role in the repair of DNA double-strand breaks and collapsed replication forks1. HR depends on the products of several paralogues of RAD51, including the tetrameric complex of RAD51B, RAD51C, RAD51D and XRCC2 (BCDX2)2. BCDX2 functions as a mediator of nucleoprotein filament assembly by RAD51 and single-stranded DNA (ssDNA) during HR, but its mechanism remains undefined. Here we report cryogenic electron microscopy reconstructions of human BCDX2 in apo and ssDNA-bound states. The structures reveal how the amino-terminal domains of RAD51B, RAD51C and RAD51D participate in inter-subunit interactions that underpin complex formation and ssDNA-binding specificity. Single-molecule DNA curtain analysis yields insights into how BCDX2 enhances RAD51–ssDNA nucleoprotein filament assembly. Moreover, our cryogenic electron microscopy and functional analyses explain how RAD51C alterations found in patients with cancer3–6 inactivate DNA binding and the HR mediator activity of BCDX2. Our findings shed light on the role of BCDX2 in HR and provide a foundation for understanding how pathogenic alterations in BCDX2 impact genome repair.

Date: 2023
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DOI: 10.1038/s41586-023-06219-w

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