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

Petra Van Der Lelij,Opher Gileadi,Johannes Zuber,Norbert Kraut,Matthias Hinterndorfer,Vittorio Katis,Simone Lieb,Mark A Pearson,Gerd Bader,Thomas Hoffmann,Julian Jude,Mark Petronczki,Jan-Michael Peters,Joseph A Newman

doi:10.26508/lsa.202000725

Petra Van Der Lelij, Opher Gileadi + Show 12 more

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https://doi.org/10.26508/lsa.202000725

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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.

Highlights

Pan-cancer genome studies have identified recurrent mutations in the cohesin complex and its regulators in a variety of human cancers (Lawrence et al, 2014; Leiserson et al, 2015)
Cohesin complexes containing STAG1 and STAG2 are important for sister chromatid cohesion at telomeres and centromeres, respectively, whereas both complexes appear to contribute to cohesion along chromosome arms (Canudas & Smith, 2009; Remeseiro et al, 2012)
We chose the near-haploid KBM-7 human leukemia line to serve as our primary screening model, as functional ablation of the vast majority of genes requires only one CRISPR/ Cas9–induced loss-of-function mutation (Burckstummer et al, 2013)

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Pan-cancer genome studies have identified recurrent mutations in the cohesin complex and its regulators in a variety of human cancers (Lawrence et al, 2014; Leiserson et al, 2015). Cohesin is a multi-subunit protein complex that is essential for sister chromatid cohesion from DNA replication to mitosis. This function of cohesin is crucial for chromosome segregation and the generation of viable daughter cells during cell division (Guacci et al, 1997; Michaelis et al, 1997). The complex consists of a tripartite ring comprising SMC1, SMC3, and RAD21 ( called SCC1 or Mcd1), which associates with a conserved peripheral fourth subunit that, in human somatic cells, is represented by two paralogs of the Scc3/STAG protein family, STAG1 or STAG2 (Losada et al, 2000; Sumara et al, 2000; Roig et al, 2014). STAG1 and STAG2, function redundantly in somatic mammalian cells to mediate sister chromatid cohesion, an event essential for cell viability during proliferation

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