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

DOI: 10.26508/lsa.202000725 DOI Help

Authors: Petra Van Der Lelij (Vienna BioCenter (VBC)) , Joseph A. Newman (Structural Genomics Consortium, University of Oxford) , Simone Lieb (Boehringer Ingelheim Regional Center Vienna (RCV) GmbH & Co KG) , Julian Jude (Vienna BioCenter (VBC)) , Vittorio Katis (Structural Genomic Consortium, Oxford University) , Thomas Hoffmann (Vienna BioCenter (VBC)) , Matthias Hinterndorfer (Vienna BioCenter (VBC)) , Gerd Bader (Boehringer Ingelheim Regional Center Vienna (RCV) GmbH & Co KG) , Norbert Kraut (Boehringer Ingelheim Regional Center Vienna (RCV) GmbH & Co KG) , Mark A. Pearson (Boehringer Ingelheim Regional Center Vienna (RCV) GmbH & Co KG) , Jan-michael Peters (Vienna BioCenter (VBC); Medical University of Vienna) , Johannes Zuber (Vienna BioCenter (VBC); Medical University of Vienna) , Opher Gileadi (Structural Genomics Consortium, University of Oxford) , Mark Petronczki (Boehringer Ingelheim Regional Center Vienna (RCV) GmbH & Co KG)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Life Science Alliance , VOL 3

State: Published (Approved)
Published: May 2020
Diamond Proposal Number(s): 19301 , 18145

Open Access Open Access

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.

Journal Keywords: Structural Biology; Cell Biology; Cancer

Subject Areas: Biology and Bio-materials


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I24-Microfocus Macromolecular Crystallography

Documents:
e202000725.full.pdf