Faculty, Staff and Student Publications
Publication Date
3-8-2024
Journal
Nature Communications
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.
Keywords
Animals, Humans, Mice, DNA, DNA Replication, Genomic Instability, GRB2 Adaptor Protein, Immunity, Innate, MRE11 Homologue Protein, Neoplasms, Rad51 Recombinase, DNA recombination, Breast cancer, DNA damage response
Included in
Bioinformatics Commons, Biological Phenomena, Cell Phenomena, and Immunity Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Genetic Processes Commons, Genomics Commons, Medical Genetics Commons, Medical Immunology Commons, Oncology Commons
Comments
Supplementary Materials
Data Availability Statement
PMID: 38459011