Journal article

Cohesin mutations are synthetic lethal with stimulation of WNT signaling

Chue Vin Chin, Jisha Antony, Sarada Ketharnathan, Anastasia Labudina, Gregory Gimenez, Kate M Parsons, Jinshu He, Amee J George, Maria Michela Pallotta, Antonio Musio, Antony Braithwaite, Parry Guilford, Ross D Hannan, Julia A Horsfield

eLife | ELIFE SCIENCES PUBLICATIONS LTD | Published : 2020

Abstract

Mutations in genes encoding subunits of the cohesin complex are common in several cancers, but may also expose druggable vulnerabilities. We generated isogenic MCF10A cell lines with deletion mutations of genes encoding cohesin subunits SMC3, RAD21, and STAG2 and screened for synthetic lethality with 3009 FDA-approved compounds. The screen identified several compounds that interfere with transcription, DNA damage repair and the cell cycle. Unexpectedly, one of the top 'hits' was a GSK3 inhibitor, an agonist of Wnt signaling. We show that sensitivity to GSK3 inhibition is likely due to stabilization of β-catenin in cohesin-mutant cells, and that Wnt-responsive gene expression is highly sensit..

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Grants

Awarded by Health Research Council of New Zealand


Awarded by Associazione Italiana


Awarded by Maurice Wilkins centre for Molecular Biodiscovery


Funding Acknowledgements

Health Research Council of New Zealand 15/229 Julia A HorsfieldHealth Research Council of New Zealand 19/415 Ross D Hannan Julia A HorsfieldAssociazione Italiana per la IG23284 Antonio MusioRicerca sul CancroThe Maurice Wilkins centre for Molecular Biodiscovery 3705733 Jisha Antony Julia A HorsfieldThe funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.