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

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 () and Zamal Ahmed ()
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Zu Ye: The University of Texas MD Anderson Cancer Center
Shengfeng Xu: The University of Texas MD Anderson Cancer Center
Yin Shi: Zhejiang University School of Medicine
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

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46283-y

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