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GRB2 stabilizes RAD51 at reversed replication forks suppressing genomic instability and innate immunity against cancer

Author

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  • Zu Ye

    (The University of Texas MD Anderson Cancer Center
    Chinese Academy of Sciences)

  • Shengfeng Xu

    (The University of Texas MD Anderson Cancer Center)

  • Yin Shi

    (Zhejiang University School of Medicine
    The University of Texas MD Anderson Cancer Center)

  • Xueqian Cheng

    (The University of Texas MD Anderson Cancer Center)

  • Yuan Zhang

    (The University of Texas MD Anderson Cancer Center)

  • Sunetra Roy

    (University of Texas MD Anderson Cancer Center)

  • Sarita Namjoshi

    (The University of Texas MD Anderson Cancer Center)

  • Michael A. Longo

    (The University of Texas MD Anderson Cancer Center)

  • Todd M. Link

    (The University of Texas MD Anderson Cancer Center)

  • Katharina Schlacher

    (University of Texas MD Anderson Cancer Center)

  • Guang Peng

    (The University of Texas MD Anderson Cancer Center)

  • Dihua Yu

    (The University of Texas MD Anderson Cancer Center)

  • Bin Wang

    (The University of Texas MD Anderson Cancer Center)

  • John A. Tainer

    (The University of Texas MD Anderson Cancer Center)

  • Zamal Ahmed

    (The University of Texas MD Anderson Cancer Center)

Abstract

Growth factor receptor-bound protein 2 (GRB2) is a cytoplasmic adapter for tyrosine kinase signaling and a nuclear adapter for homology-directed-DNA repair. Here we find nuclear GRB2 protects DNA at stalled replication forks from MRE11-mediated degradation in the BRCA2 replication fork protection axis. Mechanistically, GRB2 binds and inhibits RAD51 ATPase activity to stabilize RAD51 on stalled replication forks. In GRB2-depleted cells, PARP inhibitor (PARPi) treatment releases DNA fragments from stalled forks into the cytoplasm that activate the cGAS–STING pathway to trigger pro-inflammatory cytokine production. Moreover in a syngeneic mouse metastatic ovarian cancer model, GRB2 depletion in the context of PARPi treatment reduced tumor burden and enabled high survival consistent with immune suppression of cancer growth. Collective findings unveil GRB2 function and mechanism for fork protection in the BRCA2-RAD51-MRE11 axis and suggest GRB2 as a potential therapeutic target and an enabling predictive biomarker for patient selection for PARPi and immunotherapy combination.

Suggested Citation

  • Zu Ye & Shengfeng Xu & Yin Shi & Xueqian Cheng & Yuan Zhang & Sunetra Roy & Sarita Namjoshi & Michael A. Longo & Todd M. Link & Katharina Schlacher & Guang Peng & Dihua Yu & Bin Wang & John A. Tainer , 2024. "GRB2 stabilizes RAD51 at reversed replication forks suppressing genomic instability and innate immunity against cancer," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46283-y
    DOI: 10.1038/s41467-024-46283-y
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