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

ABSTRACT: 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-? 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.

SUBMITTER: Viswanathan SR

PROVIDER: S-EPMC6143899 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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

Viswanathan Srinivas R SR Nogueira Marina F MF Buss Colin G CG Krill-Burger John M JM Wawer Mathias J MJ Malolepsza Edyta E Berger Ashton C AC Choi Peter S PS Shih Juliann J Taylor Alison M AM Tanenbaum Benjamin B Pedamallu Chandra Sekhar CS Cherniack Andrew D AD Tamayo Pablo P Strathdee Craig A CA Lage Kasper K Carr Steven A SA Schenone Monica M Bhatia Sangeeta N SN Vazquez Francisca F Tsherniak Aviad A Hahn William C WC Meyerson Matthew M

Nature genetics 20180628 7

Functional redundancy shared by paralog genes may afford protection against genetic perturbations, but it can also result in genetic vulnerabilities due to mutual interdependency<sup>1-5</sup>. 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<sup>6-8</sup>. MAGOHB is the top gene dependency in cells with hemiz ...[more]

PMID: 29955178

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Project description:Viswanathan SR, Nogueira MF, Buss CG, Krill-Burger JM, Wawer MJ, Malolepsza E, Choi PS, Berger A, Shih J, Tanenbaum B, Strathdee CA, Tamayo P, Pedamallu CS, Vazquez F, Lage K, Carr SA, Schenone M, Bhatia SN, Cherniack AD, Tsherniak A, Hahn WC, Meyerson M. Nature Genetics 2018. Chromosome arm-level deletion events are highly prevalent across cancer types. The targeting of functionally redundant paralog genes required for cell viability has been proposed as a potential therapeutic strategy to selectively kill cancer cells with chromosome arm deletions. Here, we identify MAGOHB as a novel therapeutic target for chromosome 1p deleted cancer through an analysis of paralog dependencies emerging from genome-wide shRNA screening of cancer cell lines. MAGOHB and its functionally redundant paralog, MAGOH, are core members of the exon-junction complex (EJC), a multi-protein complex that is deposited at exon-exon junctions after mRNA splicing and that has important roles in regulating pre-mRNA splicing, mRNA transport, and nonsense-mediated decay (NMD) MAGOHB is the top differential dependency in cells with hemizygous loss of MAGOH, a pervasive passenger genetic event across multiple tumor types that frequently occurs in the context of chromosome 1p loss. Inhibition of MAGOHB in cells with deletion of MAGOH compromises viability by globally perturbing alternative splicing and RNA surveillance, resulting in an accumulation of premature-termination codon-containing transcripts. We further identify IPO13, a bidirectional karyopherin that mediates nuclear import of the MAGOH/B-Y14 heterodimer as a potentially druggable target whose dependency is highly correlated to both MAGOH and MAGOHB dependency, suggesting a rationale for inhibiting MAGOH/MAGOHB function by interfering with EJC recycling. Finally, we validate MAGOHB as a target in vivo through delivery of a tumor-penetrating peptide-siRNA nanocomplex. Our results define MAGOH and MAGOHB as reciprocal paralog dependencies across cancer types and identify the MAGOHB-IPO13 axis as an potential therapeutic target in MAGOH-deleted cancers and in cancers with chromosome 1p deletion.

Dataset Information

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

Publications

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

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