6RRK

Crystal structure of the central region of human cohesin subunit STAG1 in complex with RAD21 peptide

Summary for 6RRK

• Entry DOI: 10.2210/pdb6rrk/pdb
• Descriptor: Cohesin subunit SA-1, Double-strand-break repair protein rad21 homolog (2 entities in total)
• Functional Keywords: cohesin, stromal antigen, chromatid, gene regulation
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 114895.27

Authors

Newman, J.A.,katis, V.L.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.,Bountra, C.,Gileadi, O. (deposition date: 2019-05-20, release date: 2019-06-26, Last modification date: 2024-01-24)

Primary citation

van der Lelij, P.,Newman, J.A.,Lieb, S.,Jude, J.,Katis, V.,Hoffmann, T.,Hinterndorfer, M.,Bader, G.,Kraut, N.,Pearson, M.A.,Peters, J.M.,Zuber, J.,Gileadi, O.,Petronczki, M.
STAG1 vulnerabilities for exploiting cohesin synthetic lethality in STAG2-deficient cancers.
Life Sci Alliance, 3:-, 2020

PubMed Abstract: The cohesin subunit has emerged as a recurrently inactivated tumor suppressor in human cancers. Using candidate approaches, recent studies have revealed a synthetic lethal interaction between and its paralog 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 -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 -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 -mutated tumors.

PubMed: 32467316
DOI: 10.26508/lsa.202000725

Experimental method

X-RAY DIFFRACTION (3.17 Å)