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

• Published in: Nature genetics Vol. 50; no. 7; pp. 937 - 943
• Main Authors: Viswanathan, Srinivas R., Nogueira, Marina F., Buss, Colin G., Krill-Burger, John M., Wawer, Mathias J., Malolepsza, Edyta, Berger, Ashton C., Choi, Peter S., Shih, Juliann, Taylor, Alison M., Tanenbaum, Benjamin, Pedamallu, Chandra Sekhar, Cherniack, Andrew D., Tamayo, Pablo, Strathdee, Craig A., Lage, Kasper, Carr, Steven A., Schenone, Monica, Bhatia, Sangeeta N., Vazquez, Francisca, Tsherniak, Aviad, Hahn, William C., Meyerson, Matthew
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2018; Nature Publishing Group
• Subjects: 13; 13/106; 45/47; 45/91; 631/208/505; 631/337/505; 631/67/1059/602; 96; Acids; Agriculture; Alternative splicing; Animal Genetics and Genomics; Animals; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer cells; Cancer genetics; Cancer Research; Cancer screening; Cell Line, Tumor; Cell Nucleus - genetics; Chromosome 1; Chromosome deletion; Chromosomes; Chromosomes, Human, Pair 1; Clonal deletion; Consortia; CRISPR; Datasets; Dependence; Exons - genetics; Female; Gene Deletion; Gene Function; Genes; Genetic research; Genetic testing; Genomes; Genomics; HEK293 Cells; Human Genetics; Humans; Intelligence gathering; Karyopherins - genetics; Lethal mutation; Lethality; Letter; Mice; Mice, Nude; Neoplasms - genetics; Nuclear Proteins - genetics; Nuclear transport; Ontology; Redundancy; Ribonucleic acid; RNA; RNA Splicing - genetics; RNA, Small Interfering - genetics; Splicing; Tumor cell lines; Viability; Xenografts; Xenotransplantation; United States > US
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/s41588-018-0155-3

Functional redundancy shared by paralog genes may afford protection against genetic perturbations, but it can also result in genetic vulnerabilities due to mutual interdependency 1 – 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 dependencies 6 – 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 heterodimer 9 , 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. Analysis of paralog gene pairs using data from loss-of-function genetic screens in cancer cells identifies MAGOH and MAGOHB as reciprocal paralog dependencies across cancer types.