The VEGF receptor neuropilin 2 promotes homologous recombination by stimulating YAP/TAZ-mediated Rad51 expression
AuthorsElaimy, Ameer L.
Amante, John J.
Zhu, Lihua Julie
Fitzgerald, Thomas J.
Goel, Hira Lal
Mercurio, Arthur M.
UMass Chan AffiliationsDepartment of Radiation Oncology
Medical Scientist Training Program
Department of Molecular, Cell and Cancer Biology
Amino Acids, Peptides, and Proteins
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AbstractVascular endothelial growth factor (VEGF) signaling in tumor cells mediated by neuropilins (NRPs) contributes to the aggressive nature of several cancers, including triple-negative breast cancer (TNBC), independently of its role in angiogenesis. Understanding the mechanisms by which VEGF-NRP signaling contributes to the phenotype of such cancers is a significant and timely problem. We report that VEGF-NRP2 promote homologous recombination (HR) in BRCA1 wild-type TNBC cells by contributing to the expression and function of Rad51, an essential enzyme in the HR pathway that mediates efficient DNA double-strand break repair. Mechanistically, we provide evidence that VEGF-NRP2 stimulates YAP/TAZ-dependent Rad51 expression and that Rad51 is a direct YAP/TAZ-TEAD transcriptional target. We also discovered that VEGF-NRP2-YAP/TAZ signaling contributes to the resistance of TNBC cells to cisplatin and that Rad51 rescues the defects in DNA repair upon inhibition of either VEGF-NRP2 or YAP/TAZ. These findings reveal roles for VEGF-NRP2 and YAP/TAZ in DNA repair, and they indicate a unified mechanism involving VEGF-NRP2, YAP/TAZ, and Rad51 that contributes to resistance to platinum chemotherapy.
Elaimy AL, Amante JJ, Zhu LJ, Wang M, Walmsley CS, FitzGerald TJ, Goel HL, Mercurio AM. The VEGF receptor neuropilin 2 promotes homologous recombination by stimulating YAP/TAZ-mediated Rad51 expression. Proc Natl Acad Sci U S A. 2019 Jul 9;116(28):14174-14180. doi: 10.1073/pnas.1821194116. Epub 2019 Jun 24. PMID: 31235595; PMCID: PMC6628806. Link to article on publisher's site