2. Academic Validation
  3. STAG1 vulnerabilities for exploiting cohesin synthetic lethality in STAG2-deficient cancers

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

  • Life Sci Alliance. 2020 May 28;3(7):e202000725. doi: 10.26508/lsa.202000725.
Petra van der Lelij 1,  Joseph A Newman 2,  Simone Lieb 3,  Julian Jude 1,  Vittorio Katis 2,  Thomas Hoffmann 1,  Matthias Hinterndorfer 1,  Gerd Bader 3,  Norbert Kraut 3,  Mark A Pearson 3,  Jan-Michael Peters 1 4,  Johannes Zuber 5 4,  Opher Gileadi 6,  Mark Petronczki 7
Affiliations

Affiliations

  • 1 Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Vienna, Austria.
  • 2 Structural Genomics Consortium, University of Oxford, Oxford, UK.
  • 3 Boehringer Ingelheim Regional Center Vienna (RCV) GmbH & Co KG, Vienna, Austria.
  • 4 Medical University of Vienna, VBC, Vienna, Austria.
  • 5 Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Vienna, Austria johannes.zuber@imp.ac.at.
  • 6 Structural Genomics Consortium, University of Oxford, Oxford, UK opher.gileadi@sgc.ox.ac.uk.
  • 7 Boehringer Ingelheim Regional Center Vienna (RCV) GmbH & Co KG, Vienna, Austria mark_paul.petronczki@boehringer-ingelheim.com.
PMID: 32467316 DOI: 10.26508/lsa.202000725
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.

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