RT Journal Article SR Electronic T1 STAG1 vulnerabilities for exploiting cohesin synthetic lethality in STAG2-deficient cancers JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202000725 DO 10.26508/lsa.202000725 VO 3 IS 7 A1 van der Lelij, Petra A1 Newman, Joseph A A1 Lieb, Simone A1 Jude, Julian A1 Katis, Vittorio A1 Hoffmann, Thomas A1 Hinterndorfer, Matthias A1 Bader, Gerd A1 Kraut, Norbert A1 Pearson, Mark A A1 Peters, Jan-Michael A1 Zuber, Johannes A1 Gileadi, Opher A1 Petronczki, Mark YR 2020 UL http://www.life-science-alliance.org/content/3/7/e202000725.abstract 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.