biostudies-literatureAbd El-Hafeez AANCATS NIH HHSNIDDK NIH HHSNIAID NIH HHSNHLBI NIH HHSNCI NIH HHSNINDS NIH HHSNIGMS NIH HHS105973https://www.ebi.ac.uk/biostudies/studies/S-EPMC9900518biostudies-literatureUnknown26(2)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.iScienceRegulation of DNA damage response by trimeric G-proteins.PMC9900518T32 CA121938R01 CA238042R33 CA225549R01 CA238023R56 NS073976R01 CA160911R01 DK107585T32 CA067754R01 GM117424R01 AI118985R37 CA222563R01 CA100768R01 AI141630R01 NS073976R01 HL145477UG3 TR002968U01 CA210152R50 CA221807Sun NRajapakse NLuker GDAbd El-Hafeez AAChamarthi PHazra TKDas SLuker KEGhosh PRoy SChakraborty AEar JfalseRegulation of DNA damage response by trimeric G-proteins.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.2023-01-01T00:00:00Z2023 Feb2026-05-29T03:35:53.764Z2025-04-06T19:10:30.024ZS-EPMC99005183675637810.1016/j.isci.2023.105973