Identification and characterization of hippuristanol-resistant mutants reveals eIF4A1 dependencies within mRNA 5 ' leader regions

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dc.contributor.authorSteinberger, Jutta
dc.contributor.authorShen, Leo
dc.contributor.authorKiniry, Stephen J.
dc.contributor.authorNaineni, Sai Kiran
dc.contributor.authorCencic, Regina
dc.contributor.authorAmiri, Mehdi
dc.contributor.authorAboushawareb, Sarah A. E.
dc.contributor.authorChu, Jennifer
dc.contributor.authorMaiga, Rayelle Itoua
dc.contributor.authorYachnin, Brahm J.
dc.contributor.authorRobert, Francis
dc.contributor.authorSonenberg, Nahum
dc.contributor.authorBaranov, Pavel V.
dc.contributor.authorPelletier, Jerry
dc.contributor.funderHealth Research Boarden
dc.contributor.funderScience Foundation Irelanden
dc.contributor.funderWellcome Trusten
dc.contributor.funderCanadian Institutes of Health Researchen
dc.date.accessioned2022-07-20T09:44:35Z
dc.date.available2022-07-20T09:44:35Z
dc.date.issued2020-09
dc.date.updated2022-07-20T09:23:46Z
dc.description.abstractHippuristanol (Hipp) is a natural product that selectively inhibits protein synthesis by targeting eukaryotic initiation factor (eIF) 4A, a DEAD-box RNA helicase required for ribosome recruitment to mRNA templates. Hipp binds to the carboxyl-terminal domain of eIF4A, locks it in a closed conformation, and inhibits its RNA binding. The dependencies of mRNAs for eIF4A during initiation is contingent on the degree of secondary structure within their 5' leader region. Interest in targeting eIF4A therapeutically in cancer and viral-infected settings stems from the dependencies that certain cellular (e.g. pro-oncogenic, pro-survival) and viral mRNAs show towards eIF4A. Using a CRISPR/Cas9-based variomics screen, we identify functional EIF4A1 Hipp-resistant alleles, which in turn allowed us to link the translation-inhibitory and cytotoxic properties of Hipp to eIF4A1 target engagement. Genome-wide translational profiling in the absence or presence of Hipp were undertaken and our validation studies provided insight into the structure-activity relationships of eIF4A-dependent mRNAs. We find that mRNA 5' leader length, overall secondary structure and cytosine content are defining features of Hipp-dependent mRNAs.en
dc.description.sponsorshipCanadian Institutes of Health Research (CIHR) Foundation (Grant FDN-148366)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationSteinberger, J., Shen, L., Kiniry, S. J., Naineni, S. K., Cencic, R., Amiri, M., Aboushawareb, S. A. E., Chu, J., Maiga, R. I., Yachnin, B. J., Robert, F., Sonenberg, N., Baranov, P. V. and Pelletier, J.(2020) 'Identification and characterization of hippuristanol-resistant mutants reveals eIF4A1 dependencies within mRNA 5 ' leader regions', Nucleic Acids Research, 48 (17), pp. 9521-9537. doi: 10.1093/nar/gkaa662en
dc.identifier.doi10.1093/nar/gkaa662en
dc.identifier.endpage9537en
dc.identifier.issn0305-1048
dc.identifier.issued17en
dc.identifier.journaltitleNucleic acids researchen
dc.identifier.startpage9521en
dc.identifier.urihttps://hdl.handle.net/10468/13379
dc.identifier.volume48en
dc.language.isoenen
dc.publisherOxford University Pressen
dc.relation.projectinfo:eu-repo/grantAgreement/WT/Molecular Basis of Cell Function/210692//Molecular memory in human AMD1 gene: mechanisms and functions./en
dc.rights© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subjectEukaryotic translation initiationen
dc.subjectSmall-molecule inhibitionen
dc.subjectTherapeutic suppressionen
dc.subjectHelicaseen
dc.subjectBindingen
dc.titleIdentification and characterization of hippuristanol-resistant mutants reveals eIF4A1 dependencies within mRNA 5 ' leader regionsen
dc.typeArticle (peer-reviewed)en
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