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Nat Genet DOI:10.1038/s41588-018-0155-3

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

Publication TypeJournal Article
Year of Publication2018
AuthorsViswanathan, SR, Nogueira, MF, Buss, CG, Krill-Burger, JM, Wawer, MJ, Malolepsza, E, Berger, AC, Choi, PS, Shih, J, Taylor, AM, Tanenbaum, B, Pedamallu, CSekhar, Cherniack, AD, Tamayo, P, Strathdee, CA, Lage, K, Carr, SA, Schenone, M, Bhatia, SN, Vazquez, F, Tsherniak, A, Hahn, WC, Meyerson, M
JournalNat Genet
Date Published2018 07
KeywordsAnimals, Cell Line, Tumor, Cell Nucleus, Chromosomes, Human, Pair 1, Exons, Female, Gene Deletion, HEK293 Cells, Humans, Karyopherins, Mice, Mice, Nude, Neoplasms, Nuclear Proteins, RNA Splicing, RNA, Small Interfering

Functional redundancy shared by paralog genes may afford protection against genetic perturbations, but it can also result in genetic vulnerabilities due to mutual interdependency. 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. 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, 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.


Alternate JournalNat Genet
PubMed ID29955178
PubMed Central IDPMC6143899
Grant ListR01 GM123313 / GM / NIGMS NIH HHS / United States
R35 CA197568 / CA / NCI NIH HHS / United States
U01 CA217885 / CA / NCI NIH HHS / United States
U01 CA176058 / CA / NCI NIH HHS / United States
P30 ES002109 / ES / NIEHS NIH HHS / United States
R01 HG009285 / HG / NHGRI NIH HHS / United States
K99 CA208028 / CA / NCI NIH HHS / United States
R01 CA222826 / CA / NCI NIH HHS / United States
U24 CA194107 / CA / NCI NIH HHS / United States
T32 CA009172 / CA / NCI NIH HHS / United States
P30 CA014051 / CA / NCI NIH HHS / United States