Survival of BRCA2-Deficient Cells Is Promoted by GIPC3, a Novel Genetic Interactor of BRCA2.

4 years ago

Survival of BRCA2-Deficient Cells Is Promoted by GIPC3, a Novel Genetic Interactor of BRCA2.

Zhou, Ding, Pamala, Sharan, Morrison, Burkett, Martin, Ritt, Pang, Swing, Philip, Ji

BRCA2 loss-of-heterozygosity (LOH) is frequently observed in BRCA2-mutated tumors, but its bi-allelic 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 BRCA2, such as TRP53, 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 GIPC3 (GAIP-interacting protein C-terminus 3) as a BRCA2 genetic interactor that contributes to survival of Brca2-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 Brca2-null 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 Brca2-null embryos with Gipc3 overexpression are developmentally more advanced than their control littermates. Taken together, we have uncovered a novel role for GIPC3 as a BRCA2 genetic interactor.

Publisher URL: http://doi.org/10.1534/genetics.117.300357

DOI: 10.1534/genetics.117.300357