TY - JOUR T1 - Hardwired synthetic lethality within the cohesin complex in human cancer cells JF - bioRxiv DO - 10.1101/125708 SP - 125708 AU - Petra van der Lelij AU - Simone Lieb AU - Julian Jude AU - Gordana Wutz AU - Catarina P. Santos AU - Katrina Falkenberg AU - Andreas Schlattl AU - Jozef Ban AU - Raphaela Schwentner AU - Heinrich Kovar AU - Francisco X. Real AU - Todd Waldman AU - Mark A. Pearson AU - Norbert Kraut AU - Jan-Michael Peters AU - Johannes Zuber AU - Mark Petronczki Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/04/08/125708.abstract N2 - Recent genome analyses have identified recurrent mutations in the cohesin complex in a wide range of human cancers. Here we demonstrate that the most frequently mutated subunit of the cohesin complex, STAG2, displays a strong synthetic lethal interaction with its paralog STAG1. Mechanistically, STAG1 loss abrogates sister chromatid cohesion in STAG2 mutated but not in wild-type cells leading to mitotic catastrophe, defective cell division and apoptosis. STAG1 inactivation inhibits the proliferation of STAG2 mutated but not wild-type bladder cancer and Ewing sarcoma cell lines. Restoration of STAG2 expression in a mutated bladder cancer model alleviates the dependency on STAG1. Thus, STAG1 and STAG2 act redundantly to support sister chromatid cohesion and cell survival. STAG1 represents a hardwired, context independent vulnerability of cancer cells carrying mutations in the major emerging tumor suppressor STAG2. Exploiting synthetic lethal interactions to target recurrent cohesin mutations in cancer, e.g. by inhibiting STAG1, holds the promise for the development of selective therapeutics. ER -