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

View ORCID ProfilePetra 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  Correspondence email, Opher Gileadi  Correspondence email, View ORCID ProfileMark Petronczki  Correspondence email
Petra van der Lelij
1Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Vienna, Austria
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  • ORCID record for Petra van der Lelij
Joseph A Newman
2Structural Genomics Consortium, University of Oxford, Oxford, UK
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Simone Lieb
3Boehringer Ingelheim Regional Center Vienna (RCV) GmbH & Co KG, Vienna, Austria
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Julian Jude
1Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Vienna, Austria
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Vittorio Katis
2Structural Genomics Consortium, University of Oxford, Oxford, UK
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Thomas Hoffmann
1Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Vienna, Austria
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Matthias Hinterndorfer
1Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Vienna, Austria
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Gerd Bader
3Boehringer Ingelheim Regional Center Vienna (RCV) GmbH & Co KG, Vienna, Austria
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Norbert Kraut
3Boehringer Ingelheim Regional Center Vienna (RCV) GmbH & Co KG, Vienna, Austria
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Mark A Pearson
3Boehringer Ingelheim Regional Center Vienna (RCV) GmbH & Co KG, Vienna, Austria
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Jan-Michael Peters
1Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Vienna, Austria
4Medical University of Vienna, VBC, Vienna, Austria
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Johannes Zuber
1Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Vienna, Austria
4Medical University of Vienna, VBC, Vienna, Austria
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  • For correspondence: johannes.zuber@imp.ac.at
Opher Gileadi
2Structural Genomics Consortium, University of Oxford, Oxford, UK
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  • For correspondence: opher.gileadi@sgc.ox.ac.uk
Mark Petronczki
3Boehringer Ingelheim Regional Center Vienna (RCV) GmbH & Co KG, Vienna, Austria
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  • For correspondence: mark_paul.petronczki@boehringer-ingelheim.com
Published 28 May 2020. DOI: 10.26508/lsa.202000725
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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.

  • Received March 31, 2020.
  • Revision received May 13, 2020.
  • Accepted May 14, 2020.
  • © 2020 van der Lelij et al.
Creative Commons logoCreative Commons logohttps://creativecommons.org/licenses/by/4.0/

This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).

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Exploiting cohesin synthetic lethality
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 May 2020, 3 (7) e202000725; DOI: 10.26508/lsa.202000725

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Exploiting cohesin synthetic lethality
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 May 2020, 3 (7) e202000725; DOI: 10.26508/lsa.202000725
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Volume 3, No. 7
July 2020
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