RT Journal Article SR Electronic T1 Paralogous synthetic lethality underlies genetic dependencies of the cancer-mutated gene STAG2 JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202101083 DO 10.26508/lsa.202101083 VO 4 IS 11 A1 Melanie L Bailey A1 David Tieu A1 Andrea Habsid A1 Amy Hin Yan Tong A1 Katherine Chan A1 Jason Moffat A1 Philip Hieter YR 2021 UL https://www.life-science-alliance.org/content/4/11/e202101083.abstract AB STAG2, a component of the mitotically essential cohesin complex, is highly mutated in several different tumour types, including glioblastoma and bladder cancer. Whereas cohesin has roles in many cancer-related pathways, such as chromosome instability, DNA repair and gene expression, the complex nature of cohesin function has made it difficult to determine how STAG2 loss might either promote tumorigenesis or be leveraged therapeutically across divergent cancer types. Here, we have performed whole-genome CRISPR-Cas9 screens for STAG2-dependent genetic interactions in three distinct cellular backgrounds. Surprisingly, STAG1, the paralog of STAG2, was the only negative genetic interaction that was shared across all three backgrounds. We also uncovered a paralogous synthetic lethal mechanism behind a genetic interaction between STAG2 and the iron regulatory gene IREB2. Finally, investigation of an unusually strong context-dependent genetic interaction in HAP1 cells revealed factors that could be important for alleviating cohesin loading stress. Together, our results reveal new facets of STAG2 and cohesin function across a variety of genetic contexts.