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

Nat Genet
Authors
Keywords
Abstract

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.

Year of Publication
2018
Journal
Nat Genet
Volume
50
Issue
7
Pages
937-943
Date Published
2018 07
ISSN
1546-1718
DOI
10.1038/s41588-018-0155-3
PubMed ID
29955178
PubMed Central ID
PMC6143899
Links
Grant list
R01 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