PT  - JOURNAL ARTICLE
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  - Thomas Hoffmann
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
TI  - Synthetic lethality between the cohesin subunits <em>STAG1</em> and <em>STAG2</em> in diverse cancer contexts
AID  - 10.1101/155309
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 155309
4099  - http://biorxiv.org/content/early/2017/06/25/155309.short
4100  - http://biorxiv.org/content/early/2017/06/25/155309.full
AB  - 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 support sister chromatid cohesion to redundantly ensure cell survival. STAG1 represents a vulnerability of cancer cells carrying mutations in the major emerging tumor suppressor STAG2 across different cancer contexts. 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.