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

Author

Listed:
  • 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
    University of Texas Health Science Center at San Antonio)

  • 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
    University of Texas Health Science Center at San Antonio)

  • 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
    University of Texas Health Science Center at San Antonio)

  • Li Lan

    (Harvard Medical School
    Duke University)

  • Bing Xia

    (Rutgers Cancer Institute of New Jersey and Robert Wood Johnson Medical School)

  • Weixing Zhao

    (University of Texas Health and Science Center
    University of Texas Health Science Center at San Antonio)

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.

Suggested Citation

  • 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 & , 2024. "DSS1 restrains BRCA2’s engagement with dsDNA for homologous recombination, replication fork protection, and R-loop homeostasis," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51557-6
    DOI: 10.1038/s41467-024-51557-6
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