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dc.contributor.authorLiu, Y.
dc.contributor.authorXu, H.
dc.contributor.authorVan der Jeught, K.
dc.date.accessioned2019-06-21T18:46:26Z
dc.date.available2019-06-21T18:46:26Z
dc.date.issued2018
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85049834063&doi=10.1172%2fJCI98727&partnerID=40&md5=d52d2ed86e78a935cea7de71195c5218
dc.identifier.urihttp://hdl.handle.net/10713/9686
dc.description.abstractA synthetic lethality-based strategy has been developed to identify therapeutic targets in cancer harboring tumor-suppressor gene mutations, as exemplified by the effectiveness of poly ADP-ribose polymerase (PARP) inhibitors in BRCA1/2-mutated tumors. However, many synthetic lethal interactors are less reliable due to the fact that such genes usually do not perform fundamental or indispensable functions in the cell. Here, we developed an approach to identifying the "essential lethality" arising from these mutated/deleted essential genes, which are largely tolerated in cancer cells due to genetic redundancy. We uncovered the cohesion subunit SA1 as a putative synthetic-essential target in cancers carrying inactivating mutations of its paralog, SA2. In SA2-deficient Ewing sarcoma and bladder cancer, further depletion of SA1 profoundly and specifically suppressed cancer cell proliferation, survival, and tumorigenic potential. Mechanistically, inhibition of SA1 in the SA2-mutated cells led to premature chromatid separation, dramatic extension of mitotic duration, and consequently, lethal failure of cell division. More importantly, depletion of SA1 rendered those SA2-mutated cells more susceptible to DNA damage, especially double-strand breaks (DSBs), due to reduced functionality of DNA repair. Furthermore, inhibition of SA1 sensitized the SA2-deficient cancer cells to PARP inhibitors in vitro and in vivo, providing a potential therapeutic strategy for patients with SA2-deficient tumors. Copyright 2018 American Society for Clinical Investigation. All rights reserved.en_US
dc.description.sponsorshipThis work was funded in part by US NIH grants R01CA203737 (to XL) and R01CA206366 (to XH and XL), the Vera Bradley Foundation (to XL), National Natural Science Foundation of China grant 81620108030 (to GJ), and the Indiana University Strategic Research Initiative fund (to XL).en_US
dc.description.urihttps://dx.doi.org/10.1172/JCI98727en_US
dc.language.isoen-USen_US
dc.publisherAmerican Society for Clinical Investigationen_US
dc.relation.ispartofJournal of Clinical Investigation
dc.subjectSA2-deficient tumorsen_US
dc.subject.meshGenes, Tumor Suppressoren_US
dc.titleSomatic mutation of the cohesin complex subunit confers therapeutic vulnerabilities in canceren_US
dc.typeArticleen_US
dc.identifier.doi10.1172/JCI98727
dc.identifier.pmid29649003


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