Synthetic lethality between the cohesin subunitsSTAG1andSTAG2in diverse cancer contexts

Abstract

. CC-BY 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/155309 doi: bioRxiv preprint first posted online Jun. 25, 2017; 3 Main textCohesin is a highly conserved ring-shaped protein complex that is thought to topologically embrace chromatid fibers (Peters & Nishiyama, 2012), which is essential for sister chromatid cohesion and chromosome segregation in eukaryotes. In addition, cohesin participates in DNA repair, genome organization and gene expression (Losada, 2014). The cohesin subunits SMC1, SMC3 and RAD21 (also called SCC1) comprise the core ring of the complex. A fourth universally conserved subunit, a HEAT repeat protein of the Scc3/STAG family, peripherally associates with the core cohesin ring by binding to RAD21 (Toth et al., 1999), and is required for the dynamic association of cohesin with chromatin (Hu et al., 2011;Murayama & Uhlmann, 2014). Human somatic cells express two paralogs of this protein, called STAG1 and STAG2 (Losada, Yokochi, Kobayashi, & Hirano, 2000;Sumara, Vorlaufer, Gieffers, Peters, & Peters, 2000).Recent cancer genome studies identified recurrent mutations in cohesin subunits and regulators in approximately 7.3% of all human cancers (Lawrence et al., 2014; Leiserson et al., 2015;Solomon et al., 2011). STAG2, the most frequently mutated cohesin subunit, emerges as one of only 12 genes that are significantly mutated in 4 or more major human malignancies (Lawrence et al., 2014). STAG2 mutations have been reported in ~6% of acute myeloid leukemias and myelodysplastic syndromes (Kon et al., 2013; Thota et al., 2014; Walter et al., 2012), 15-22% of Ewing's sarcomas (Brohl et al., 2014; Crompton et al., 2014;Tirode et al., 2014), and in up to 26% of bladder cancers of various stages and grades (Balbas-Martinez et al., 2013; Guo et al., 2013;Solomon et al., 2013;Taylor, Platt, Hurst, Thygesen, & Knowles, 2014). The deleterious nature of most STAG2 mutations strongly suggests that the gene represents a new tumor suppressor . STAG2 mutations were initially thought to promote tumorigenesis due to defects in sister chromatid cohesin leading to genome instability (Barber et al., 2008;Solomon et al., 2011). However, the vast majority of cohesin-mutated cancers are euploid (Balbas-Martinez et . CC-BY 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/155309 doi: bioRxiv preprint first posted online Jun. 25, 2017; 4 al., 2013;Kon et al., 2013), indicating that cohesin mutations may promote tumorigenesis through altering different cohesin functions such as genome organization and transcriptional regulation (Galeev et al., 2016; Mazumdar et al., 2015;Mullenders et al., 2015; Viny et al., 2015). Regardless of the mechanisms driving cohesin mutant tumors, the recent success of poly(ADP-ribose) polymerase inhibitors in the treatment of BRCA-mutated o...

STAG2 cohesin is essential for heart morphogenesis

“…In summary, we here show that cells lacking cohesin-STAG2 are viable both in vitro (tissue culture) and in vivo (in embryos and adult tissues), confirming that cohesin-STAG1 is sufficient to fulfill essential cohesin functions ( 8, 9 ). However, their decreased proliferation and altered transcriptomes lead to embryonic lethality, a result that provides further compelling evidence for cell- and tissue-specific roles of the two cohesin complexes and how their dysfunction may contribute to disease.…”

“…Results in human cells are in line with these findings, although the extent of cohesion defects reported in the absence of STAG2 is variable. In any case, a single variant is sufficient to maintain cell viability in culture ( 6, 8, 9 ).…”

Somatic mutation of the cohesin complex subunit confers therapeutic vulnerabilities in cancer

“…Inhibition of SA1 as a potential therapeutic approach was first suggested in cell-based studies (50,51). However, all the variables and complexity of the in vivo tumor environment need to be considered before this approach can be considered for further therapeutic translation.…”

Redundant and specific roles of cohesin STAG subunits in chromatin looping and transcription control

“…Moreover, SA2 is required for DNA damage repair via the homologous recombination pathway in the S/G2 cell cycle phases (Kong et al 2014), but both SA1 and SA2 are necessary for the S-phase DNA damage checkpoint (Kong et al 2014). Cells can tolerate the absence of either SA1 or SA2 alone but not of both simultaneously, suggesting that SA1 and SA2 have at least partially redundant roles (Hill et al 2016;Benedetti et al 2017;van der Lelij et al 2017).…”