RT Journal Article
SR Electronic
T1 Hardwired synthetic lethality within the cohesin complex in human cancer cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 125708
DO 10.1101/125708
A1 Petra van der Lelij
A1 Simone Lieb
A1 Julian Jude
A1 Gordana Wutz
A1 Catarina P. Santos
A1 Katrina Falkenberg
A1 Andreas Schlattl
A1 Jozef Ban
A1 Raphaela Schwentner
A1 Heinrich Kovar
A1 Francisco X. Real
A1 Todd Waldman
A1 Mark A. Pearson
A1 Norbert Kraut
A1 Jan-Michael Peters
A1 Johannes Zuber
A1 Mark Petronczki
YR 2017
UL http://biorxiv.org/content/early/2017/04/08/125708.abstract
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 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.