Genome-scale analysis identifies paralog lethality as a vulnerability of chromosome 1p loss in cancer.*

Dependency Map image; Credit: Tom Ulrich

Cancer Dependency Map (Credit: Broad Institute of MIT and Harvard)

Viswanathan SR, Nogueira MF, Buss CG, Krill-Burger JM, Wawer MJ, Malolepsza E, Berger AC, Choi PS, Shih J, Taylor AM, Tanenbaum B, Pedamallu CS, Cherniack AD, Tamayo P, Strathdee CA, Lage K, Carr SA, Schenone M, Bhatia SN, Vazquez F, Tsherniak A, Hahn WC, Meyerson M.

Nature Genetics

July 01, 2018

Functional redundancy shared by paralog genes may afford protection against genetic perturbations, but it can also result in genetic vulnerabilities due to mutual interdependency1-5. Here, we surveyed genome-scale short hairpin RNA and CRISPR screening data on hundreds of cancer cell lines and identified MAGOH and MAGOHB, core members of the splicing-dependent exon junction complex, as top-ranked paralog dependencies6-8. MAGOHB is the top gene dependency in cells with hemizygous MAGOH deletion, a pervasive genetic event that frequently occurs due to chromosome 1p loss. Inhibition of MAGOHB in a MAGOH-deleted context compromises viability by globally perturbing alternative splicing and RNA surveillance. Dependency on IPO13, an importin-β receptor that mediates nuclear import of the MAGOH/B-Y14 heterodimer9, is highly correlated with dependency on both MAGOH and MAGOHB. Both MAGOHB and IPO13 represent dependencies in murine xenografts with hemizygous MAGOH deletion. Our results identify MAGOH and MAGOHB as reciprocal paralog dependencies across cancer types and suggest a rationale for targeting the MAGOHB-IPO13 axis in cancers with chromosome 1p deletion.

Last updated: June 28, 2020