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

doi:10.1016/j.isci.2023.105973

Regulation of DNA damage response by trimeric G-proteins

iScience. 2023 Jan 13;26(2):105973. doi: 10.1016/j.isci.2023.105973. eCollection 2023 Feb 17.

Authors

Amer Ali Abd El-Hafeez^{1

2}, Nina Sun¹, Anirban Chakraborty³, Jason Ear^{1

4}, Suchismita Roy¹, Pranavi Chamarthi¹, Navin Rajapakse¹, Soumita Das⁵, Kathryn E Luker⁶, Tapas K Hazra³, Gary D Luker^{6

7

8}, Pradipta Ghosh^{1

9

10

11}

Affiliations

¹ Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA.
² Pharmacology and Experimental Oncology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt.
³ Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA.
⁴ Biological Sciences Department, California State Polytechnic University, Pomona, CA 91768, USA.
⁵ Department of Pathology, University of California San Diego, La Jolla, CA 92093, USA.
⁶ Center for Molecular Imaging, Department of Radiology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA.
⁷ Department of Biomedical Engineering, University of Michigan, 2200 Bonisteel, Blvd., Ann Arbor, MI 48109-2099, USA.
⁸ Department of Microbiology and Immunology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA.
⁹ Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
¹⁰ Moores Comprehensive Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
¹¹ Veterans Affairs Medical Center, La Jolla, CA, USA.

Abstract

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.

Keywords: Biological sciences; Cell biology; Molecular biology.

Abstract

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