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 sensitized in STAG2-mutant CMK leukemia cells. Moreover, Wnt activity is enhanced in zebrafish mutant for cohesin subunits stag2b and rad21. Our results suggest that cohesin mutations could progress oncogenesis by enhancing Wnt signaling, and that targeting the Wnt pathway may represent a novel therapeutic strategy for cohesin-mutant cancers.
Highlights
The cohesin complex is essential for sister chromatid cohesion, DNA replication, DNA repair, and genome organization
Homozygous loss of STAG2 was determined by the absence of STAG2 mRNA and protein (Supplementary Fig. 1e-g)
The cohesin complex and its regulators are encoded by several different loci, and genetic alterations in any one of them may occur in up to 26% of patients included in The Cancer
Summary
The cohesin complex is essential for sister chromatid cohesion, DNA replication, DNA repair, and genome organization. SMC1A, SMC3 and RAD21, form the core ring-shaped structure of human cohesin [1, 2]. A fourth subunit of either STAG1 or STAG2 binds to cohesin by contacting RAD21 and SMC subunits [3], and is required for the association of cohesin with DNA [1-3]. The STAG subunits of cohesin are capable of binding RNA in the nucleus [4]. Cohesin associates with DNA by interaction with loading factors NIPBL and MAU2 [5], its stability on DNA is regulated by the acetyltransferases. The cohesin ring itself acts as a molecular motor to extrude DNA loops, and this activity is thought to underlie its ability to organize the genome [10, 11].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
