PT - JOURNAL ARTICLE AU - van der Lelij, Petra AU - Newman, Joseph A AU - Lieb, Simone AU - Jude, Julian AU - Katis, Vittorio AU - Hoffmann, Thomas AU - Hinterndorfer, Matthias AU - Bader, Gerd AU - Kraut, Norbert AU - Pearson, Mark A AU - Peters, Jan-Michael AU - Zuber, Johannes AU - Gileadi, Opher AU - Petronczki, Mark TI - STAG1 vulnerabilities for exploiting cohesin synthetic lethality in STAG2-deficient cancers AID - 10.26508/lsa.202000725 DP - 2020 Jul 01 TA - Life Science Alliance PG - e202000725 VI - 3 IP - 7 4099 - http://www.life-science-alliance.org/content/3/7/e202000725.short 4100 - http://www.life-science-alliance.org/content/3/7/e202000725.full SO - Life Sci. Alliance2020 Jul 01; 3 AB - The cohesin subunit STAG2 has emerged as a recurrently inactivated tumor suppressor in human cancers. Using candidate approaches, recent studies have revealed a synthetic lethal interaction between STAG2 and its paralog STAG1. To systematically probe genetic vulnerabilities in the absence of STAG2, we have performed genome-wide CRISPR screens in isogenic cell lines and identified STAG1 as the most prominent and selective dependency of STAG2-deficient cells. Using an inducible degron system, we show that chemical genetic degradation of STAG1 protein results in the loss of sister chromatid cohesion and rapid cell death in STAG2-deficient cells, while sparing STAG2–wild-type cells. Biochemical assays and X-ray crystallography identify STAG1 regions that interact with the RAD21 subunit of the cohesin complex. STAG1 mutations that abrogate this interaction selectively compromise the viability of STAG2-deficient cells. Our work highlights the degradation of STAG1 and inhibition of its interaction with RAD21 as promising therapeutic strategies. These findings lay the groundwork for the development of STAG1-directed small molecules to exploit synthetic lethality in STAG2-mutated tumors.