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.