PT  - JOURNAL ARTICLE
AU  - Melanie L Bailey
AU  - David Tieu
AU  - Andrea Habsid
AU  - Amy Hin Yan Tong
AU  - Katherine Chan
AU  - Jason Moffat
AU  - Philip Hieter
TI  - Paralogous synthetic lethality underlies genetic dependencies of the cancer-mutated gene <em>STAG2</em>
AID  - 10.26508/lsa.202101083
DP  - 2021 Nov 01
TA  - Life Science Alliance
PG  - e202101083
VI  - 4
IP  - 11
4099  - https://www.life-science-alliance.org/content/4/11/e202101083.short
4100  - https://www.life-science-alliance.org/content/4/11/e202101083.full
SO  - Life Sci. Alliance2021 Nov 01; 4
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.