%0 Journal Article %A Petra van der Lelij %A Joseph A Newman %A Simone Lieb %A Julian Jude %A Vittorio Katis %A Thomas Hoffmann %A Matthias Hinterndorfer %A Gerd Bader %A Norbert Kraut %A Mark A Pearson %A Jan-Michael Peters %A Johannes Zuber %A Opher Gileadi %A Mark Petronczki %T STAG1 vulnerabilities for exploiting cohesin synthetic lethality in STAG2-deficient cancers %D 2020 %R 10.26508/lsa.202000725 %J Life Science Alliance %P e202000725 %V 3 %N 7 %X 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. %U https://www.life-science-alliance.org/content/lsa/3/7/e202000725.full.pdf