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Nat Genet. 2018 Jul;50(7):937-943. doi: 10.1038/s41588-018-0155-3. Epub 2018 Jun 28.

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

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
2
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
3
Harvard Medical School, Boston, MA, USA.
4
Harvard-MIT Department of Health Sciences and Technology, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Boston, MA, USA.
5
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
6
Chemical Biology and Therapeutics Science Program, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
7
Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
8
UCSD Moores Cancer Center and Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
9
Howard Hughes Medical Institute, Chevy Chase, MD, USA.
10
Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
11
Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
12
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. matthew_meyerson@dfci.harvard.edu.
13
Broad Institute of MIT and Harvard, Cambridge, MA, USA. matthew_meyerson@dfci.harvard.edu.
14
Harvard Medical School, Boston, MA, USA. matthew_meyerson@dfci.harvard.edu.

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-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.

PMID:
29955178
PMCID:
PMC6143899
[Available on 2018-12-28]
DOI:
10.1038/s41588-018-0155-3

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