Author
Listed:
- 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
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
Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases)
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.
Suggested Citation
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. , 2023.
"Structural insights into BCDX2 complex function in homologous recombination,"
Nature, Nature, vol. 619(7970), pages 640-649, July.
Handle:
RePEc:nat:nature:v:619:y:2023:i:7970:d:10.1038_s41586-023-06219-w
DOI: 10.1038/s41586-023-06219-w
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