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dc.contributor.authorMarini, A
dc.contributor.authorRotblat, B
dc.contributor.authorSbarrato, T
dc.contributor.authorNiklison-Chirou, MV
dc.contributor.authorKnight, JRP
dc.contributor.authorDudek, K
dc.contributor.authorJones, C
dc.contributor.authorBushell, M
dc.contributor.authorKnight, RA
dc.contributor.authorAmelio, I
dc.contributor.authorWillis, AE
dc.contributor.authorMelino, G
dc.date.accessioned2018-10-01T08:42:18Z
dc.date.available2018-10-01T08:42:18Z
dc.date.issued2018-06-12
dc.identifier.issn0027-8424
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/282982
dc.description.abstractTAp73 is a transcription factor that plays key roles in brain development, aging, and cancer. At the cellular level, TAp73 is a critical homeostasis-maintaining factor, particularly following oxidative stress. Although major studies focused on TAp73 transcriptional activities have indicated a contribution of TAp73 to cellular metabolism, the mechanisms underlying its role in redox homeostasis have not been completely elucidated. Here we show that TAp73 contributes to the oxidative stress response by participating in the control of protein synthesis. Regulation of mRNA translation occupies a central position in cellular homeostasis during the stress response, often by reducing global rates of protein synthesis and promoting translation of specific mRNAs. TAp73 depletion results in aberrant ribosomal RNA (rRNA) processing and impaired protein synthesis. In particular, polysomal profiles show that TAp73 promotes the integration of mRNAs that encode rRNA-processing factors in polysomes, supporting their translation. Concurrently, TAp73 depletion causes increased sensitivity to oxidative stress that correlates with reduced ATP levels, hyperactivation of AMPK, and translational defects. TAp73 is important for maintaining active translation of mitochondrial transcripts in response to oxidative stress, thus promoting mitochondrial activity. Our results indicate that TAp73 contributes to redox homeostasis by affecting the translational machinery, facilitating the translation of specific mitochondrial transcripts. This study identifies a mechanism by which TAp73 contributes to the oxidative stress response and describes a completely unexpected role for TAp73 in regulating protein synthesis.
dc.languageeng
dc.publisherProceedings of the National Academy of Sciences
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectROS
dc.subjectTAp73
dc.subjectmitochondria
dc.subjectp53 family
dc.subjecttranslation
dc.subjectA549 Cells
dc.subjectHEK293 Cells
dc.subjectHumans
dc.subjectMitochondria
dc.subjectOxidative Stress
dc.subjectProtein Biosynthesis
dc.subjectReactive Oxygen Species
dc.subjectTOR Serine-Threonine Kinases
dc.subjectTumor Protein p73
dc.titleTAp73 contributes to the oxidative stress response by regulating protein synthesis.
dc.typeArticle
prism.endingPage6224
prism.issueIdentifier24
prism.publicationDate2018
prism.publicationNameProc Natl Acad Sci U S A
prism.startingPage6219
prism.volume115
dc.identifier.doi10.17863/CAM.30344
rioxxterms.versionofrecord10.1073/pnas.1718531115
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-06-12
dc.contributor.orcidAmelio, Ivano [0000-0002-9126-5391]
dc.contributor.orcidWillis, Anne [0000-0002-1470-8531]
dc.contributor.orcidMelino, Gerry [0000-0001-9428-5972]
dc.identifier.eissn1091-6490
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMRC (TOX GRA 06 02 013)
pubs.funder-project-idWellcome Trust (201847/Z/16/Z)
cam.issuedOnline2018-05-29


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Attribution-NonCommercial-NoDerivatives 4.0 International
Except where otherwise noted, this item's licence is described as Attribution-NonCommercial-NoDerivatives 4.0 International