Promotion of DNA end resection by BRCA1–BARD1 in homologous recombination

Sameer Salunkhe, James M. Daley (), Hardeep Kaur, Nozomi Tomimatsu, Chaoyou Xue, Vivek B. Raina, Angela M. Jasper, Cody M. Rogers, Wenjing Li, Shuo Zhou, Rahul Mojidra, Youngho Kwon, Qingming Fang, Jae-Hoon Ji, Aida Badamchi Shabestari, O’Taveon Fitzgerald, Hoang Dinh, Bipasha Mukherjee, Amyn A. Habib, Robert Hromas, Alexander V. Mazin, Elizabeth V. Wasmuth, Shaun K. Olsen, David S. Libich, Daohong Zhou, Weixing Zhao, Eric C. Greene (), Sandeep Burma () and Patrick Sung ()
Additional contact information
Sameer Salunkhe: University of Texas Health Science Center at San Antonio
James M. Daley: University of Texas Health Science Center at San Antonio
Hardeep Kaur: University of Texas Health Science Center at San Antonio
Nozomi Tomimatsu: University of Texas Health Science Center at San Antonio
Chaoyou Xue: Columbia University Irving Medical Center
Vivek B. Raina: Columbia University Irving Medical Center
Angela M. Jasper: University of Texas Health Science Center at San Antonio
Cody M. Rogers: University of Texas Health Science Center at San Antonio
Wenjing Li: University of Texas Health Science Center at San Antonio
Shuo Zhou: University of Texas Health Science Center at San Antonio
Rahul Mojidra: University of Texas Health Science Center at San Antonio
Youngho Kwon: University of Texas Health Science Center at San Antonio
Qingming Fang: University of Texas Health Science Center at San Antonio
Jae-Hoon Ji: University of Texas Health Science Center at San Antonio
Aida Badamchi Shabestari: University of Texas Health Science Center at San Antonio
O’Taveon Fitzgerald: University of Texas Health Science Center at San Antonio
Hoang Dinh: University of Texas Health Science Center at San Antonio
Bipasha Mukherjee: University of Texas Health Science Center at San Antonio
Amyn A. Habib: University of Texas Southwestern Medical Center
Robert Hromas: University of Texas Health Science Center at San Antonio
Alexander V. Mazin: University of Texas Health Science Center at San Antonio
Elizabeth V. Wasmuth: University of Texas Health Science Center at San Antonio
Shaun K. Olsen: University of Texas Health Science Center at San Antonio
David S. Libich: University of Texas Health Science Center at San Antonio
Daohong Zhou: University of Texas Health Science Center at San Antonio
Weixing Zhao: University of Texas Health Science Center at San Antonio
Eric C. Greene: Columbia University Irving Medical Center
Sandeep Burma: University of Texas Health Science Center at San Antonio
Patrick Sung: University of Texas Health Science Center at San Antonio

Nature, 2024, vol. 634, issue 8033, 482-491

Abstract: Abstract The licensing step of DNA double-strand break repair by homologous recombination entails resection of DNA ends to generate a single-stranded DNA template for assembly of the repair machinery consisting of the RAD51 recombinase and ancillary factors1. DNA end resection is mechanistically intricate and reliant on the tumour suppressor complex BRCA1–BARD1 (ref. 2). Specifically, three distinct nuclease entities—the 5′–3′ exonuclease EXO1 and heterodimeric complexes of the DNA endonuclease DNA2, with either the BLM or WRN helicase—act in synergy to execute the end resection process3. A major question concerns whether BRCA1–BARD1 directly regulates end resection. Here, using highly purified protein factors, we provide evidence that BRCA1–BARD1 physically interacts with EXO1, BLM and WRN. Importantly, with reconstituted biochemical systems and a single-molecule analytical tool, we show that BRCA1–BARD1 upregulates the activity of all three resection pathways. We also demonstrate that BRCA1 and BARD1 harbour stand-alone modules that contribute to the overall functionality of BRCA1–BARD1. Moreover, analysis of a BARD1 mutant impaired in DNA binding shows the importance of this BARD1 attribute in end resection, both in vitro and in cells. Thus, BRCA1–BARD1 enhances the efficiency of all three long-range DNA end resection pathways during homologous recombination in human cells.

Date: 2024
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DOI: 10.1038/s41586-024-07910-2

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