GIV/Girdin binds BRCA1 and links trimeric G-proteins to DNA damage response

Summary Upon sensing DNA double-strand breaks (DSBs), eukaryotic cells either die or repair DSBs via one of two competing pathways, i.e., non-homologous end-joining (NHEJ) or homologous recombination (HR). We show that cell fate after DNA damage hinges on two functions of GIV/Girdin, a guanine nucleotide-exchange modulator of heterotrimeric G-protein, Giα•βγ. First, 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. Second, GIV promotes NHEJ, and binds and activates Gi and enhances the ‘free’ Gβγ→PI-3-kinase→Akt pathway, thus revealing the enigmatic origin of prosurvival Akt signals during dsDNA repair. Absence of GIV, or the loss of either of its two functions impaired DNA repair, and induced cell death when challenged with numerous cytotoxic agents. That GIV selectively binds few other BRCT-containing proteins suggests convergent signaling such that heterotrimeric G-proteins may finetune sensing, repair, and outcome after DNA damage. Significance Statement To tide of any stress, temporospatially segregated signaling pathways in cells are often scaffolded to generate cooperativity between unlikely pathways. Here we report such an unexpected crosstalk that is orchestrated via a non-receptor multimodular G protein activator, GIV/Girdin, which decisively skews the functions of BRCA1 and the choice of cellular responses after DNA damage. GIV binds and sequesters BRCA1 away from dsDNA breaks, suppressing HR. In addition, activation of trimeric Gi by GIV enhances Akt signals, favoring NHEJ. These findings reveal a hitherto unknown link between a major hub in DNA repair (i.e., BRCA1) and a signaling hub of paramount importance in essentially all aspects of modern medicine (i.e., trimeric G proteins). GRAPHIC ABSTRACT HIGHLIGHTS Non-receptor G protein modulator, GIV/Girdin binds BRCA1 Binding occurs in both canonical and non-canonical modes GIV sequesters BRCA1 away from dsDNA breaks, suppresses HR Activation of Gi by GIV enhances Akt signals, favors NHEJ IN BRIEF In this work, the authors show that heterotrimeric G protein signaling that is triggered by non-receptor GEF, GIV/Girdin, in response to double-stranded DNA breaks is critical for decisive signaling events which favor non-homologous end-joining (NHEJ) and inhibit homologous recombination (HR).