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

iScience (Feb 2023)

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

Journal volume & issue: Vol. 26, no. 2
p. 105973

Abstract

Read online

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.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

About the journal

Abstract

Keywords