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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


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.

Original languageEnglish (US)
Article number105973
Issue number2
StatePublished - Feb 17 2023


  • Biological sciences
  • Cell biology
  • Molecular biology

ASJC Scopus subject areas

  • General


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