Survival of BRCA2-Deficient Cells Is Promoted by , a Novel Genetic Interactor of .

loss-of-heterozygosity (LOH) is frequently observed in -mutated tumors, but its biallelic loss causes embryonic lethality in mice and inhibits proliferation of normal somatic cells. Therefore, it remains unclear how loss of BRCA2 contributes to tumorigenesis. One possibility is that mutation in potential genetic interactors of , such as , is required for cell survival/proliferation in the absence of BRCA2. In this study, using an insertional mutagenesis screen in mouse embryonic stem cells (mESC), we have identified (GAIP-interacting protein C-terminus 3) as a genetic interactor that contributes to survival of -null mESC. GIPC3 does not compensate for BRCA2 loss in the repair of double-strand breaks. Mass-spectrometric analysis resulted in the identification of G-protein signaling transducers, APPL1 and APPL2, as potential GIPC3-binding proteins. A mutant GIPC3 (His155Ala) that does not bind to APPL1/2 failed to rescue the lethality of mESC, suggesting that the cell viability by GIPC3 is mediated via APPL1/2. Finally, the physiological significance of GIPC3 as a genetic interactor of BRCA2 is supported by the observation that -null embryos with overexpression are developmentally more advanced than their control littermates. Taken together, we have uncovered a novel role for as a genetic interactor.