Regulation of DNA damage response by trimeric G-proteins
Amer Ali Abd El-Hafeez,
Nina Sun,
Anirban Chakraborty,
Jason Ear,
Suchismita Roy,
Pranavi Chamarthi,
Navin Rajapakse,
Soumita Das,
Kathryn E. Luker,
Tapas K. Hazra,
Gary D. Luker,
Pradipta Ghosh
Affiliations
Amer Ali Abd El-Hafeez
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA; Pharmacology and Experimental Oncology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
Nina Sun
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA
Anirban Chakraborty
Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA
Jason Ear
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA; Biological Sciences Department, California State Polytechnic University, Pomona, CA 91768, USA
Suchismita Roy
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA
Pranavi Chamarthi
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA
Navin Rajapakse
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA
Soumita Das
Department of Pathology, University of California San Diego, La Jolla, CA 92093, USA
Kathryn E. Luker
Center for Molecular Imaging, Department of Radiology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA
Tapas K. Hazra
Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA
Gary D. Luker
Center for Molecular Imaging, Department of Radiology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA; Department of Biomedical Engineering, University of Michigan, 2200 Bonisteel, Blvd., Ann Arbor, MI 48109-2099, USA; Department of Microbiology and Immunology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA
Pradipta Ghosh
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA; Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Moores Comprehensive Cancer Center, University of California San Diego, La Jolla, CA 92093, USA; Veterans Affairs Medical Center, La Jolla, CA, USA; Corresponding author
Summary: Upon sensing DNA double-strand breaks (DSBs), eukaryotic cells either die or repair DSBs via one of the two competing pathways, i.e., non-homologous end-joining (NHEJ) or homologous recombination (HR). We show that cell fate after DSBs hinges on GIV/Girdin, a guanine nucleotide-exchange modulator of heterotrimeric Giα•βγ protein. GIV suppresses HR by binding and sequestering BRCA1, a key coordinator of multiple steps within the HR pathway, away from DSBs; it does so using a C-terminal motif that binds BRCA1’s BRCT-modules via both phospho-dependent and -independent mechanisms. Using another non-overlapping C-terminal motif GIV binds and activates Gi and enhances the “free” Gβγ→PI-3-kinase→Akt pathway, which promotes survival and is known to suppress HR, favor NHEJ. Absence of GIV, or loss of either of its C-terminal motifs enhanced cell death upon genotoxic stress. Because GIV selectively binds other BRCT-containing proteins suggests that G-proteins may fine-tune sensing, repair, and survival after diverse types of DNA damage.
