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Instruments / Technical Area	Publication Details	Published	Actions
I04-1-Macromolecular Crystallography (fixed wavelength) I24-Microfocus Macromolecular Crystallography	STAG1 vulnerabilities for exploiting cohesin synthetic lethality in STAG2-deficient cancers Petra Van Der Lelij , Joseph A. Newman , Simone Lieb , Julian Jude , Vittorio Katis , Thomas Hoffmann , Matthias Hinterndorfer , Gerd Bader , Norbert Kraut , Mark A. Pearson , Jan-michael Peters , Johannes Zuber , Opher Gileadi , Mark Petronczki Life Science Alliance 3 DOI: 10.26508/lsa.202000725 Diamond Proposal Number(s): [19301, 18145] Open Access Show Abstract ▼ Abstract: 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.	May 2020

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I04-1-Macromolecular Crystallography (fixed wavelength)
I24-Microfocus Macromolecular Crystallography

STAG1 vulnerabilities for exploiting cohesin synthetic lethality in STAG2-deficient cancers