DSS1 restrains BRCA2’s engagement with dsDNA for homologous recombination, replication fork protection, and R-loop homeostasis

Yuxin Huang, Wenjing Li, Tzeh Foo, Jae-Hoon Ji, Bo Wu, Nozomi Tomimatsu, Qingming Fang, Boya Gao, Melissa Long, Jingfei Xu, Rouf Maqbool, Bipasha Mukherjee, Tengyang Ni, Salvador Alejo, Yuan He, Sandeep Burma, Li Lan, Bing Xia and Weixing Zhao ()
Additional contact information
Yuxin Huang: University of Texas Health and Science Center
Wenjing Li: University of Texas Health and Science Center
Tzeh Foo: Rutgers Cancer Institute of New Jersey and Robert Wood Johnson Medical School
Jae-Hoon Ji: University of Texas Health and Science Center
Bo Wu: University of Texas Health and Science Center
Nozomi Tomimatsu: University of Texas Health Science Center at San Antonio
Qingming Fang: University of Texas Health and Science Center
Boya Gao: Harvard Medical School
Melissa Long: Harvard Medical School
Jingfei Xu: Northwestern University
Rouf Maqbool: University of Texas Health and Science Center
Bipasha Mukherjee: Rutgers Cancer Institute of New Jersey and Robert Wood Johnson Medical School
Tengyang Ni: University of Texas Health and Science Center
Salvador Alejo: University of Texas Health Science Center
Yuan He: Northwestern University
Sandeep Burma: University of Texas Health and Science Center
Li Lan: Harvard Medical School
Bing Xia: Rutgers Cancer Institute of New Jersey and Robert Wood Johnson Medical School
Weixing Zhao: University of Texas Health and Science Center

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract DSS1, essential for BRCA2-RAD51 dependent homologous recombination (HR), associates with the helical domain (HD) and OB fold 1 (OB1) of the BRCA2 DSS1/DNA-binding domain (DBD) which is frequently targeted by cancer-associated pathogenic variants. Herein, we reveal robust ss/dsDNA binding abilities in HD-OB1 subdomains and find that DSS1 shuts down HD-OB1’s DNA binding to enable ssDNA targeting of the BRCA2-RAD51 complex. We show that C-terminal helix mutations of DSS1, including the cancer-associated R57Q mutation, disrupt this DSS1 regulation and permit dsDNA binding of HD-OB1/BRCA2-DBD. Importantly, these DSS1 mutations impair BRCA2/RAD51 ssDNA loading and focus formation and cause decreased HR efficiency, destabilization of stalled forks and R-loop accumulation, and hypersensitize cells to DNA-damaging agents. We propose that DSS1 restrains the intrinsic dsDNA binding of BRCA2-DBD to ensure BRCA2/RAD51 targeting to ssDNA, thereby promoting optimal execution of HR, and potentially replication fork protection and R-loop suppression.

Date: 2024
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DOI: 10.1038/s41467-024-51557-6

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