RT Journal Article
SR Electronic
T1 STAG1 vulnerabilities for exploiting cohesin synthetic lethality in STAG2-deficient cancers
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202000725
DO 10.26508/lsa.202000725
VO 3
IS 7
A1 van der Lelij, Petra
A1 Newman, Joseph A
A1 Lieb, Simone
A1 Jude, Julian
A1 Katis, Vittorio
A1 Hoffmann, Thomas
A1 Hinterndorfer, Matthias
A1 Bader, Gerd
A1 Kraut, Norbert
A1 Pearson, Mark A
A1 Peters, Jan-Michael
A1 Zuber, Johannes
A1 Gileadi, Opher
A1 Petronczki, Mark
YR 2020
UL http://www.life-science-alliance.org/content/3/7/e202000725.abstract
AB The cohesin subunit STAG2 has emerged as a recurrently inactivated tumor suppressor in human cancers. Using candidate approaches, recent studies have revealed a synthetic lethal interaction between STAG2 and its paralog STAG1. To systematically probe genetic vulnerabilities in the absence of STAG2, we have performed genome-wide CRISPR screens in isogenic cell lines and identified STAG1 as the most prominent and selective dependency of STAG2-deficient cells. Using an inducible degron system, we show that chemical genetic degradation of STAG1 protein results in the loss of sister chromatid cohesion and rapid cell death in STAG2-deficient cells, while sparing STAG2–wild-type cells. Biochemical assays and X-ray crystallography identify STAG1 regions that interact with the RAD21 subunit of the cohesin complex. STAG1 mutations that abrogate this interaction selectively compromise the viability of STAG2-deficient cells. Our work highlights the degradation of STAG1 and inhibition of its interaction with RAD21 as promising therapeutic strategies. These findings lay the groundwork for the development of STAG1-directed small molecules to exploit synthetic lethality in STAG2-mutated tumors.