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dc.contributor.authorPitera, Aleksandra P
dc.contributor.authorSzaruga, Maria
dc.contributor.authorPeak-Chew, Sew-Yeu
dc.contributor.authorWingett, Steven W
dc.contributor.authorBertolotti, Anne
dc.date.accessioned2022-04-25T10:00:18Z
dc.date.available2022-04-25T10:00:18Z
dc.date.issued2022-06-01
dc.date.submitted2021-10-19
dc.identifier.issn0261-4189
dc.identifier.otherembj2021109985
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/336419
dc.descriptionFunder: EC | FP7 | FP7 Ideas: European Research Council (IDEE‐CER); Id: http://dx.doi.org/10.13039/100011199; Grant(s): FP7/(2007‐2013)/ERC grant 309516
dc.description.abstractHalofuginone (HF) is a phase 2 clinical compound that inhibits the glutamyl-prolyl-tRNA synthetase (EPRS) thereby inducing the integrated stress response (ISR). Here, we report that halofuginone indeed triggers the predicted canonical ISR adaptations, consisting of attenuation of protein synthesis and gene expression reprogramming. However, the former is surprisingly atypical and occurs to a similar magnitude in wild-type cells, cells lacking GCN2 and those incapable of phosphorylating eIF2α. Proline supplementation rescues the observed HF-induced changes indicating that they result from inhibition of EPRS. The failure of the GCN2-to-eIF2α pathway to elicit a measurable protective attenuation of translation initiation allows translation elongation defects to prevail upon HF treatment. Exploiting this vulnerability of the ISR, we show that cancer cells with increased proline dependency are more sensitive to halofuginone. This work reveals that the consequences of EPRS inhibition are more complex than anticipated and provides novel insights into ISR signaling, as well as a molecular framework to guide the targeted development of halofuginone as a therapeutic.
dc.languageen
dc.publisherEMBO
dc.subjectEMBO03
dc.subjectEMBO08
dc.subjectEMBO32
dc.subjectArticle
dc.subjectArticles
dc.subjectGCN2
dc.subjectintegrated stress response
dc.subjectstress responses
dc.subjecttranslation
dc.subjecttRNA synthetase
dc.titleCellular responses to halofuginone reveal a vulnerability of the GCN2 branch of the integrated stress response.
dc.typeArticle
dc.date.updated2022-04-25T10:00:17Z
prism.publicationNameEMBO J
dc.identifier.doi10.17863/CAM.83836
dcterms.dateAccepted2022-03-26
rioxxterms.versionofrecord10.15252/embj.2021109985
rioxxterms.versionAO
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidPitera, Aleksandra P [0000-0001-7004-1615]
dc.contributor.orcidSzaruga, Maria [0000-0003-1673-1855]
dc.contributor.orcidPeak-Chew, Sew-Yeu [0000-0002-7602-6384]
dc.contributor.orcidWingett, Steven W [0000-0002-2343-0711]
dc.contributor.orcidBertolotti, Anne [0000-0002-9185-0558]
dc.identifier.eissn1460-2075
pubs.funder-project-idUKRI | Medical Research Council (MRC) (MC_U105185860)
pubs.funder-project-idWellcome Trust (WT) (206367/Z/ 17/Z)
pubs.funder-project-idHuman Frontier Science Program (LT000162/2021‐L)
pubs.funder-project-idEuropean Molecular Biology Organization (ALTF 698‐2020)
cam.issuedOnline2022-04-25


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