Ribosome and protein synthesis are major metabolic events that control cellular growth and proliferation. Impairment in ribosome biogenesis pathways and mRNA translation is associated with pathologies such as cancer and developmental disorders. Processes that control global protein synthesis are tightly regulated at different levels by numerous factors and linked with multiple cellular signaling pathways. Several of these merge on the growth promoting factor c-Myc, which induces ribosome biogenesis by stimulating Pol I, Pol II, and Pol III transcription. However, how cells sense and respond to mRNA translation stress is not well understood. It was more recently shown that mRNA translation stress activates c-Myc, through a specific induction of E2F1 synthesis via a PI3Kδ-dependent pathway. This review focuses on how this novel feedback pathway stimulates cellular growth and proliferation pathways to synchronize protein synthesis with ribosome biogenesis. It also describes for the first time the oncogenic activity of the mRNA, and not the encoded protein.

Department of Medical Biosciences Building 6M Umeå University 901 85 Umeå Sweden

ICCVS University of Gdańsk Science ul Wita Stwosza 63 80 308 Gdańsk Poland

Inserm UMRS1162 Institut de Génétique Moléculaire Université Paris 7 Hôpital St Louis F 75010 Paris France

RECAMO Masaryk Memorial Cancer Institute Zluty kopec 7 65653 Brno Czech Republic

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Schmeing T.M., Ramakrishnan V. What recent ribosome structures have revealed about the mechanism of translation. Nature. 2009;461:1234–1242. doi: 10.1038/nature08403. PubMed DOI

Armache J.P., Jarasch A., Anger A.M., Villa E., Becker T., Bhushan S., Jossinet F., Habeck M., Dindar G., Franckenberg S., et al. Cryo-EM structure and rRNA model of a translating eukaryotic 80S ribosome at 5.5-A resolution. Proc. Natl. Acad. Sci. USA. 2010;107:19748–19753. doi: 10.1073/pnas.1009999107. PubMed DOI PMC

Melnikov S., Ben-Shem A., Garreau de Loubresse N., Jenner L., Yusupova G., Yusupov M. One core, two shells: Bacterial and eukaryotic ribosomes. Nat. Struct. Mol. Biol. 2012;19:560–567. doi: 10.1038/nsmb.2313. PubMed DOI

Ben-Shem A., Garreau de Loubresse N., Melnikov S., Jenner L., Yusupova G., Yusupov M. The structure of the eukaryotic ribosome at 3.0 A resolution. Science. 2011;334:1524–1529. doi: 10.1126/science.1212642. PubMed DOI

Rabl J., Leibundgut M., Ataide S.F., Haag A., Ban N. Crystal structure of the eukaryotic 40S ribosomal subunit in complex with initiation factor 1. Science. 2011;331:730–736. doi: 10.1126/science.1198308. PubMed DOI

Klinge S., Voigts-Hoffmann F., Leibundgut M., Arpagaus S., Ban N. Crystal structure of the eukaryotic 60S ribosomal subunit in complex with initiation factor 6. Science. 2011;334:941–948. doi: 10.1126/science.1211204. PubMed DOI

Yusupova G., Yusupov M. High-resolution structure of the eukaryotic 80S ribosome. Annu. Rev. Biochem. 2014;83:467–486. doi: 10.1146/annurev-biochem-060713-035445. PubMed DOI

Chandramouli P., Topf M., Menetret J.F., Eswar N., Cannone J.J., Gutell R.R., Sali A., Akey C.W. Structure of the mammalian 80S ribosome at 8.7 A resolution. Structure. 2008;16:535–548. doi: 10.1016/j.str.2008.01.007. PubMed DOI PMC

Woolford J.L., Jr., Baserga S.J. Ribosome biogenesis in the yeast Saccharomyces cerevisiae. Genetics. 2013;195:643–681. doi: 10.1534/genetics.113.153197. PubMed DOI PMC

Natchiar S.K., Myasnikov A.G., Kratzat H., Hazemann I., Klaholz B.P. Visualization of chemical modifications in the human 80S ribosome structure. Nature. 2017;551:472–477. doi: 10.1038/nature24482. PubMed DOI

Natchiar S.K., Myasnikov A.G., Hazemann I., Klaholz B.P. Visualizing the Role of 2’-OH rRNA Methylations in the Human Ribosome Structure. Biomolecules. 2018;8 doi: 10.3390/biom8040125. PubMed DOI PMC

Pelletier J., Thomas G., Volarevic S. Ribosome biogenesis in cancer: New players and therapeutic avenues. Nat. Rev. Cancer. 2018;18:51–63. doi: 10.1038/nrc.2017.104. PubMed DOI

Gentilella A., Kozma S.C., Thomas G. A liaison between mTOR signaling, ribosome biogenesis and cancer. Biochim. Biophys. Acta. 2015;1849:812–820. doi: 10.1016/j.bbagrm.2015.02.005. PubMed DOI PMC

Tschochner H., Hurt E. Pre-ribosomes on the road from the nucleolus to the cytoplasm. Trends Cell Biol. 2003;13:255–263. doi: 10.1016/S0962-8924(03)00054-0. PubMed DOI

Ogle J.M., Ramakrishnan V. Structural insights into translational fidelity. Annu. Rev. Biochem. 2005;74:129–177. doi: 10.1146/annurev.biochem.74.061903.155440. PubMed DOI

Zaher H.S., Green R. Fidelity at the molecular level: Lessons from protein synthesis. Cell. 2009;136:746–762. doi: 10.1016/j.cell.2009.01.036. PubMed DOI PMC

Tafforeau L., Zorbas C., Langhendries J.L., Mullineux S.T., Stamatopoulou V., Mullier R., Wacheul L., Lafontaine D.L. The complexity of human ribosome biogenesis revealed by systematic nucleolar screening of Pre-rRNA processing factors. Mol. Cell. 2013;51:539–551. doi: 10.1016/j.molcel.2013.08.011. PubMed DOI

Wild T., Horvath P., Wyler E., Widmann B., Badertscher L., Zemp I., Kozak K., Csucs G., Lund E., Kutay U. A protein inventory of human ribosome biogenesis reveals an essential function of exportin 5 in 60S subunit export. PLoS Biol. 2010;8:e1000522. doi: 10.1371/journal.pbio.1000522. PubMed DOI PMC

Badertscher L., Wild T., Montellese C., Alexander L.T., Bammert L., Sarazova M., Stebler M., Csucs G., Mayer T.U., Zamboni N., et al. Genome-wide RNAi Screening Identifies Protein Modules Required for 40S Subunit Synthesis in Human Cells. Cell Rep. 2015;13:2879–2891. doi: 10.1016/j.celrep.2015.11.061. PubMed DOI

O’Donohue M.F., Choesmel V., Faubladier M., Fichant G., Gleizes P.E. Functional dichotomy of ribosomal proteins during the synthesis of mammalian 40S ribosomal subunits. J. Cell Biol. 2010;190:853–866. doi: 10.1083/jcb.201005117. PubMed DOI PMC

Farley K.I., Baserga S.J. Probing the mechanisms underlying human diseases in making ribosomes. Biochem. Soc. Trans. 2016;44:1035–1044. doi: 10.1042/BST20160064. PubMed DOI PMC

Grummt I. Life on a planet of its own: Regulation of RNA polymerase I transcription in the nucleolus. Genes Dev. 2003;17:1691–1702. doi: 10.1101/gad.1098503R. PubMed DOI

Bodem J., Dobreva G., Hoffmann-Rohrer U., Iben S., Zentgraf H., Delius H., Vingron M., Grummt I. TIF-IA, the factor mediating growth-dependent control of ribosomal RNA synthesis, is the mammalian homolog of yeast Rrn3p. EMBO Rep. 2000;1:171–175. doi: 10.1093/embo-reports/kvd032. PubMed DOI PMC

Derenzini M., Montanaro L., Trere D. Ribosome biogenesis and cancer. Acta Histochem. 2017;119:190–197. doi: 10.1016/j.acthis.2017.01.009. PubMed DOI

Brighenti E., Trere D., Derenzini M. Targeted cancer therapy with ribosome biogenesis inhibitors: A real possibility? Oncotarget. 2015;6:38617–38627. doi: 10.18632/oncotarget.5775. PubMed DOI PMC

Stepanchick A., Zhi H., Cavanaugh A.H., Rothblum K., Schneider D.A., Rothblum L.I. DNA binding by the ribosomal DNA transcription factor rrn3 is essential for ribosomal DNA transcription. J. Biol. Chem. 2013;288:9135–9144. doi: 10.1074/jbc.M112.444265. PubMed DOI PMC

Kressler D., Hurt E., Bassler J. Driving ribosome assembly. Biochim. Biophys. Acta. 2010;1803:673–683. doi: 10.1016/j.bbamcr.2009.10.009. PubMed DOI

Grummt I. Wisely chosen paths–regulation of rRNA synthesis: Delivered on 30 June 2010 at the 35th FEBS Congress in Gothenburg, Sweden. FEBS J. 2010;277:4626–4639. doi: 10.1111/j.1742-4658.2010.07892.x. PubMed DOI

de la Cruz J., Karbstein K., Woolford J.L., Jr. Functions of ribosomal proteins in assembly of eukaryotic ribosomes in vivo. Annu. Rev. Biochem. 2015;84:93–129. doi: 10.1146/annurev-biochem-060614-033917. PubMed DOI PMC

Thomas G. An encore for ribosome biogenesis in the control of cell proliferation. Nat. Cell Biol. 2000;2:E71–E72. doi: 10.1038/35010581. PubMed DOI

Volarevic S., Stewart M.J., Ledermann B., Zilberman F., Terracciano L., Montini E., Grompe M., Kozma S.C., Thomas G. Proliferation, but not growth, blocked by conditional deletion of 40S ribosomal protein S6. Science. 2000;288:2045–2047. doi: 10.1126/science.288.5473.2045. PubMed DOI

Teng T., Thomas G., Mercer C.A. Growth control and ribosomopathies. Curr. Opin. Genet. Dev. 2013;23:63–71. doi: 10.1016/j.gde.2013.02.001. PubMed DOI

Stefanovsky V.Y., Pelletier G., Hannan R., Gagnon-Kugler T., Rothblum L.I., Moss T. An immediate response of ribosomal transcription to growth factor stimulation in mammals is mediated by ERK phosphorylation of UBF. Mol. Cell. 2001;8:1063–1073. doi: 10.1016/S1097-2765(01)00384-7. PubMed DOI

Stefanovsky V., Langlois F., Gagnon-Kugler T., Rothblum L.I., Moss T. Growth factor signaling regulates elongation of RNA polymerase I transcription in mammals via UBF phosphorylation and r-chromatin remodeling. Mol. Cell. 2006;21:629–639. doi: 10.1016/j.molcel.2006.01.023. PubMed DOI

Plas D.R., Thomas G. Tubers and tumors: Rapamycin therapy for benign and malignant tumors. Curr. Opin. Cell Biol. 2009;21:230–236. doi: 10.1016/j.ceb.2008.12.013. PubMed DOI

Mayer C., Zhao J., Yuan X., Grummt I. mTOR-dependent activation of the transcription factor TIF-IA links rRNA synthesis to nutrient availability. Genes Dev. 2004;18:423–434. doi: 10.1101/gad.285504. PubMed DOI PMC

Hannan K.M., Brandenburger Y., Jenkins A., Sharkey K., Cavanaugh A., Rothblum L., Moss T., Poortinga G., McArthur G.A., Pearson R.B., et al. mTOR-dependent regulation of ribosomal gene transcription requires S6K1 and is mediated by phosphorylation of the carboxy-terminal activation domain of the nucleolar transcription factor UBF. Mol. Cell. Biol. 2003;23:8862–8877. doi: 10.1128/MCB.23.23.8862-8877.2003. PubMed DOI PMC

Kantidakis T., Ramsbottom B.A., Birch J.L., Dowding S.N., White R.J. mTOR associates with TFIIIC, is found at tRNA and 5S rRNA genes, and targets their repressor Maf1. Proc. Natl. Acad. Sci. USA. 2010;107:11823–11828. doi: 10.1073/pnas.1005188107. PubMed DOI PMC

Mayer C., Grummt I. Ribosome biogenesis and cell growth: MTOR coordinates transcription by all three classes of nuclear RNA polymerases. Oncogene. 2006;25:6384–6391. doi: 10.1038/sj.onc.1209883. PubMed DOI

Iadevaia V., Liu R., Proud C.G. mTORC1 signaling controls multiple steps in ribosome biogenesis. Sem. Cell Dev. Biol. 2014;36:113–120. doi: 10.1016/j.semcdb.2014.08.004. PubMed DOI

Zinzalla V., Stracka D., Oppliger W., Hall M.N. Activation of mTORC2 by association with the ribosome. Cell. 2011;144:757–768. doi: 10.1016/j.cell.2011.02.014. PubMed DOI

Zhu J., Blenis J., Yuan J. Activation of PI3K/Akt and MAPK pathways regulates Myc-mediated transcription by phosphorylating and promoting the degradation of Mad1. Proc. Natl. Acad. Sci. USA. 2008;105:6584–6589. doi: 10.1073/pnas.0802785105. PubMed DOI PMC

Gomez-Roman N., Felton-Edkins Z.A., Kenneth N.S., Goodfellow S.J., Athineos D., Zhang J., Ramsbottom B.A., Innes F., Kantidakis T., Kerr E.R., et al. Activation by c-Myc of transcription by RNA polymerases I, II and III. Biochem. Soc. Symp. 2006;73:141–154. doi: 10.1042/bss0730141. PubMed DOI

van Riggelen J., Yetil A., Felsher D.W. MYC as a regulator of ribosome biogenesis and protein synthesis. Nat. Rev. Cancer. 2010;10:301–309. doi: 10.1038/nrc2819. PubMed DOI

Sirri V., Roussel P., Hernandez-Verdun D. In vivo release of mitotic silencing of ribosomal gene transcription does not give rise to precursor ribosomal RNA processing. J. Cell Biol. 2000;148:259–270. doi: 10.1083/jcb.148.2.259. PubMed DOI PMC

Heix J., Vente A., Voit R., Budde A., Michaelidis T.M., Grummt I. Mitotic silencing of human rRNA synthesis: Inactivation of the promoter selectivity factor SL1 by cdc2/cyclin B-mediated phosphorylation. EMBO J. 1998;17:7373–7381. doi: 10.1093/emboj/17.24.7373. PubMed DOI PMC

Sirri V., Roussel P., Hernandez-Verdun D. The mitotically phosphorylated form of the transcription termination factor TTF-1 is associated with the repressed rDNA transcription machinery. J. Cell Sci. 1999;112 Pt 19:3259–3268. PubMed

Voit R., Seiler J., Grummt I. Cooperative Action of Cdk1/cyclin B and SIRT1 Is Required for Mitotic Repression of rRNA Synthesis. PLoS Genet. 2015;11:e1005246. doi: 10.1371/journal.pgen.1005246. PubMed DOI PMC

Cavanaugh A.H., Hempel W.M., Taylor L.J., Rogalsky V., Todorov G., Rothblum L.I. Activity of RNA polymerase I transcription factor UBF blocked by Rb gene product. Nature. 1995;374:177–180. doi: 10.1038/374177a0. PubMed DOI

Voit R., Schafer K., Grummt I. Mechanism of repression of RNA polymerase I transcription by the retinoblastoma protein. Mol. Cell. Biol. 1997;17:4230–4237. doi: 10.1128/MCB.17.8.4230. PubMed DOI PMC

Hannan K.M., Hannan R.D., Smith S.D., Jefferson L.S., Lun M., Rothblum L.I. Rb and p130 regulate RNA polymerase I transcription: Rb disrupts the interaction between UBF and SL-1. Oncogene. 2000;19:4988–4999. doi: 10.1038/sj.onc.1203875. PubMed DOI

Ciarmatori S., Scott P.H., Sutcliffe J.E., McLees A., Alzuherri H.M., Dannenberg J.H., te Riele H., Grummt I., Voit R., White R.J. Overlapping functions of the pRb family in the regulation of rRNA synthesis. Mol. Cell. Biol. 2001;21:5806–5814. doi: 10.1128/MCB.21.17.5806-5814.2001. PubMed DOI PMC

White R.J., Trouche D., Martin K., Jackson S.P., Kouzarides T. Repression of RNA polymerase III transcription by the retinoblastoma protein. Nature. 1996;382:88–90. doi: 10.1038/382088a0. PubMed DOI

Felton-Edkins Z.A., Kenneth N.S., Brown T.R., Daly N.L., Gomez-Roman N., Grandori C., Eisenman R.N., White R.J. Direct regulation of RNA polymerase III transcription by RB, p53 and c-Myc. Cell Cycle. 2003;2:181–184. doi: 10.4161/cc.2.3.375. PubMed DOI

Gnanasundram S.V., Pyndiah S., Daskalogianni C., Armfield K., Nylander K., Wilson J.B., Fahraeus R. PI3Kδ activates E2F1 synthesis in response to mRNA translation stress. Nat. Commun. 2017;8:2103. doi: 10.1038/s41467-017-02282-w. PubMed DOI PMC

Harbour J.W., Luo R.X., Dei Santi A., Postigo A.A., Dean D.C. Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell. 1999;98:859–869. doi: 10.1016/S0092-8674(00)81519-6. PubMed DOI

Chen H.Z., Tsai S.Y., Leone G. Emerging roles of E2Fs in cancer: An exit from cell cycle control. Nat. Rev. Cancer. 2009;9:785–797. doi: 10.1038/nrc2696. PubMed DOI PMC

Whyte P., Buchkovich K.J., Horowitz J.M., Friend S.H., Raybuck M., Weinberg R.A., Harlow E. Association between an oncogene and an anti-oncogene: The adenovirus E1A proteins bind to the retinoblastoma gene product. Nature. 1988;334:124–129. doi: 10.1038/334124a0. PubMed DOI

Phelps W.C., Yee C.L., Munger K., Howley P.M. The human papillomavirus type 16 E7 gene encodes transactivation and transformation functions similar to those of adenovirus E1A. Cell. 1988;53:539–547. doi: 10.1016/0092-8674(88)90570-3. PubMed DOI

Felsani A., Mileo A.M., Paggi M.G. Retinoblastoma family proteins as key targets of the small DNA virus oncoproteins. Oncogene. 2006;25:5277–5285. doi: 10.1038/sj.onc.1209621. PubMed DOI

Sherr C.J., Roberts J.M. CDK inhibitors: Positive and negative regulators of G1-phase progression. Genes Dev. 1999;13:1501–1512. doi: 10.1101/gad.13.12.1501. PubMed DOI

David-Pfeuty T. The flexible evolutionary anchorage-dependent Pardee’s restriction point of mammalian cells: How its deregulation may lead to cancer. Biochim. Biophys. Acta. 2006;1765:38–66. doi: 10.1016/j.bbcan.2005.08.008. PubMed DOI

Donati G., Peddigari S., Mercer C.A., Thomas G. 5S ribosomal RNA is an essential component of a nascent ribosomal precursor complex that regulates the Hdm2-p53 checkpoint. Cell Rep. 2013;4:87–98. doi: 10.1016/j.celrep.2013.05.045. PubMed DOI PMC

Bursac S., Brdovcak M.C., Donati G., Volarevic S. Activation of the tumor suppressor p53 upon impairment of ribosome biogenesis. Biochim. Biophys. Acta. 2014;1842:817–830. doi: 10.1016/j.bbadis.2013.08.014. PubMed DOI

Deisenroth C., Zhang Y. Ribosome biogenesis surveillance: Probing the ribosomal protein-Mdm2-p53 pathway. Oncogene. 2010;29:4253–4260. doi: 10.1038/onc.2010.189. PubMed DOI

Opferman J.T., Zambetti G.P. Translational research? Ribosome integrity and a new p53 tumor suppressor checkpoint. Cell Death Differ. 2006;13:898–901. doi: 10.1038/sj.cdd.4401923. PubMed DOI

Zhang Y., Lu H. Signaling to p53: Ribosomal proteins find their way. Cancer Cell. 2009;16:369–377. doi: 10.1016/j.ccr.2009.09.024. PubMed DOI PMC

Mayer C., Grummt I. Cellular stress and nucleolar function. Cell Cycle. 2005;4:1036–1038. doi: 10.4161/cc.4.8.1925. PubMed DOI

Draptchinskaia N., Gustavsson P., Andersson B., Pettersson M., Willig T.N., Dianzani I., Ball S., Tchernia G., Klar J., Matsson H., et al. The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia. Nat. Genet. 1999;21:169–175. doi: 10.1038/5951. PubMed DOI

Ebert B.L., Pretz J., Bosco J., Chang C.Y., Tamayo P., Galili N., Raza A., Root D.E., Attar E., Ellis S.R., et al. Identification of RPS14 as a 5q− syndrome gene by RNA interference screen. Nature. 2008;451:335–339. doi: 10.1038/nature06494. PubMed DOI PMC

Farrar J.E., Vlachos A., Atsidaftos E., Carlson-Donohoe H., Markello T.C., Arceci R.J., Ellis S.R., Lipton J.M., Bodine D.M. Ribosomal protein gene deletions in Diamond-Blackfan anemia. Blood. 2011;118:6943–6951. doi: 10.1182/blood-2011-08-375170. PubMed DOI PMC

Shwachman H., Diamond L.K., Oski F.A., Khaw K.T. The Syndrome of Pancreatic Insufficiency and Bone Marrow Dysfunction. J. Pediatr. 1964;65:645–663. doi: 10.1016/S0022-3476(64)80150-5. PubMed DOI

Bolze A., Mahlaoui N., Byun M., Turner B., Trede N., Ellis S.R., Abhyankar A., Itan Y., Patin E., Brebner S., et al. Ribosomal protein SA haploinsufficiency in humans with isolated congenital asplenia. Science. 2013;340:976–978. doi: 10.1126/science.1234864. PubMed DOI PMC

Danilova N., Gazda H.T. Ribosomopathies: How a common root can cause a tree of pathologies. Dis. Models Mech. 2015;8:1013–1026. doi: 10.1242/dmm.020529. PubMed DOI PMC

Narla A., Ebert B.L. Ribosomopathies: Human disorders of ribosome dysfunction. Blood. 2010;115:3196–3205. doi: 10.1182/blood-2009-10-178129. PubMed DOI PMC

Tahmasebi S., Khoutorsky A., Mathews M.B., Sonenberg N. Translation deregulation in human disease. Nat. Rev. Mol. Cell Biol. 2018 doi: 10.1038/s41580-018-0034-x. PubMed DOI

Mills E.W., Green R. Ribosomopathies: There’s strength in numbers. Science. 2017;358 doi: 10.1126/science.aan2755. PubMed DOI

Xue S., Barna M. Specialized ribosomes: A new frontier in gene regulation and organismal biology. Nat. Rev. Mol. Cell Biol. 2012;13:355–369. doi: 10.1038/nrm3359. PubMed DOI PMC

Genuth N.R., Barna M. Heterogeneity and specialized functions of translation machinery: From genes to organisms. Nat. Rev. Genet. 2018;19:431–452. doi: 10.1038/s41576-018-0008-z. PubMed DOI PMC

Shi Z., Fujii K., Kovary K.M., Genuth N.R., Rost H.L., Teruel M.N., Barna M. Heterogeneous Ribosomes Preferentially Translate Distinct Subpools of mRNAs Genome-wide. Mol. Cell. 2017;67:71–83. doi: 10.1016/j.molcel.2017.05.021. PubMed DOI PMC

Genuth N.R., Barna M. The Discovery of Ribosome Heterogeneity and Its Implications for Gene Regulation and Organismal Life. Mol. Cell. 2018;71:364–374. doi: 10.1016/j.molcel.2018.07.018. PubMed DOI PMC

Bustelo X.R., Dosil M. Ribosome biogenesis and cancer: Basic and translational challenges. Curr. Opin. Genet. Dev. 2018;48:22–29. doi: 10.1016/j.gde.2017.10.003. PubMed DOI

Barna M., Pusic A., Zollo O., Costa M., Kondrashov N., Rego E., Rao P.H., Ruggero D. Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency. Nature. 2008;456:971–975. doi: 10.1038/nature07449. PubMed DOI PMC

Rossetti S., Hoogeveen A.T., Esposito J., Sacchi N. Loss of MTG16a (CBFA2T3), a novel rDNA repressor, leads to increased ribogenesis and disruption of breast acinar morphogenesis. J. Cell. Mol. Med. 2010;14:1358–1370. doi: 10.1111/j.1582-4934.2009.00982.x. PubMed DOI PMC

Brighenti E., Calabrese C., Liguori G., Giannone F.A., Trere D., Montanaro L., Derenzini M. Interleukin 6 downregulates p53 expression and activity by stimulating ribosome biogenesis: A new pathway connecting inflammation to cancer. Oncogene. 2014;33:4396–4406. doi: 10.1038/onc.2014.1. PubMed DOI PMC

Donati G., Bertoni S., Brighenti E., Vici M., Trere D., Volarevic S., Montanaro L., Derenzini M. The balance between rRNA and ribosomal protein synthesis up- and downregulates the tumour suppressor p53 in mammalian cells. Oncogene. 2011;30:3274–3288. doi: 10.1038/onc.2011.48. PubMed DOI

Erales J., Marchand V., Panthu B., Gillot S., Belin S., Ghayad S.E., Garcia M., Laforets F., Marcel V., Baudin-Baillieu A., et al. Evidence for rRNA 2′-O-methylation plasticity: Control of intrinsic translational capabilities of human ribosomes. Proc. Natl. Acad. Sci. USA. 2017;114:12934–12939. doi: 10.1073/pnas.1707674114. PubMed DOI PMC

Marcel V., Ghayad S.E., Belin S., Therizols G., Morel A.P., Solano-Gonzalez E., Vendrell J.A., Hacot S., Mertani H.C., Albaret M.A., et al. p53 acts as a safeguard of translational control by regulating fibrillarin and rRNA methylation in cancer. Cancer Cell. 2013;24:318–330. doi: 10.1016/j.ccr.2013.08.013. PubMed DOI PMC

Marcel V., Catez F., Diaz J.J. Ribosome heterogeneity in tumorigenesis: The rRNA point of view. Mol. Cell. Oncol. 2015;2:e983755. doi: 10.4161/23723556.2014.983755. PubMed DOI PMC

Monaco P.L., Marcel V., Diaz J.J., Catez F. 2’-O-Methylation of Ribosomal RNA: Towards an Epitranscriptomic Control of Translation? Biomolecules. 2018;8 doi: 10.3390/biom8040106. PubMed DOI PMC

Belin S., Beghin A., Solano-Gonzalez E., Bezin L., Brunet-Manquat S., Textoris J., Prats A.C., Mertani H.C., Dumontet C., Diaz J.J. Dysregulation of ribosome biogenesis and translational capacity is associated with tumor progression of human breast cancer cells. PLoS ONE. 2009;4:e7147. doi: 10.1371/journal.pone.0007147. PubMed DOI PMC

Rocchi L., Pacilli A., Sethi R., Penzo M., Schneider R.J., Trere D., Brigotti M., Montanaro L. Dyskerin depletion increases VEGF mRNA internal ribosome entry site-mediated translation. Nucleic Acids Res. 2013;41:8308–8318. doi: 10.1093/nar/gkt587. PubMed DOI PMC

Yoon A., Peng G., Brandenburger Y., Zollo O., Xu W., Rego E., Ruggero D. Impaired control of IRES-mediated translation in X-linked dyskeratosis congenita. Science. 2006;312:902–906. doi: 10.1126/science.1123835. PubMed DOI

Penzo M., Montanaro L. Turning Uridines around: Role of rRNA Pseudouridylation in Ribosome Biogenesis and Ribosomal Function. Biomolecules. 2018;8 doi: 10.3390/biom8020038. PubMed DOI PMC

Shoemaker C.J., Green R. Kinetic analysis reveals the ordered coupling of translation termination and ribosome recycling in yeast. Proc. Natl. Acad. Sci. USA. 2011;108:E1392–E1398. doi: 10.1073/pnas.1113956108. PubMed DOI PMC

Pisarev A.V., Skabkin M.A., Pisareva V.P., Skabkina O.V., Rakotondrafara A.M., Hentze M.W., Hellen C.U., Pestova T.V. The role of ABCE1 in eukaryotic posttermination ribosomal recycling. Mol. Cell. 2010;37:196–210. doi: 10.1016/j.molcel.2009.12.034. PubMed DOI PMC

Shah P., Ding Y., Niemczyk M., Kudla G., Plotkin J.B. Rate-limiting steps in yeast protein translation. Cell. 2013;153:1589–1601. doi: 10.1016/j.cell.2013.05.049. PubMed DOI PMC

Tenson T., Ehrenberg M. Regulatory nascent peptides in the ribosomal tunnel. Cell. 2002;108:591–594. doi: 10.1016/S0092-8674(02)00669-4. PubMed DOI

Wen J.D., Lancaster L., Hodges C., Zeri A.C., Yoshimura S.H., Noller H.F., Bustamante C., Tinoco I. Following translation by single ribosomes one codon at a time. Nature. 2008;452:598–603. doi: 10.1038/nature06716. PubMed DOI PMC

Simms C.L., Hudson B.H., Mosior J.W., Rangwala A.S., Zaher H.S. An active role for the ribosome in determining the fate of oxidized mRNA. Cell Rep. 2014;9:1256–1264. doi: 10.1016/j.celrep.2014.10.042. PubMed DOI PMC

Guydosh N.R., Green R. Dom34 rescues ribosomes in 3′ untranslated regions. Cell. 2014;156:950–962. doi: 10.1016/j.cell.2014.02.006. PubMed DOI PMC

Ishimura R., Nagy G., Dotu I., Zhou H., Yang X.L., Schimmel P., Senju S., Nishimura Y., Chuang J.H., Ackerman S.L. RNA function. Ribosome stalling induced by mutation of a CNS-specific tRNA causes neurodegeneration. Science. 2014;345:455–459. doi: 10.1126/science.1249749. PubMed DOI PMC

Yin Y., Manoury B., Fahraeus R. Self-inhibition of synthesis and antigen presentation by Epstein-Barr virus-encoded EBNA1. Science. 2003;301:1371–1374. doi: 10.1126/science.1088902. PubMed DOI

Apcher S., Daskalogianni C., Manoury B., Fahraeus R. Epstein Barr virus-encoded EBNA1 interference with MHC class I antigen presentation reveals a close correlation between mRNA translation initiation and antigen presentation. PLoS Pathog. 2010;6:e1001151. doi: 10.1371/journal.ppat.1001151. PubMed DOI PMC

Murat P., Zhong J., Lekieffre L., Cowieson N.P., Clancy J.L., Preiss T., Balasubramanian S., Khanna R., Tellam J. G-quadruplexes regulate Epstein-Barr virus-encoded nuclear antigen 1 mRNA translation. Nat. Chem. Biol. 2014;10:358–364. doi: 10.1038/nchembio.1479. PubMed DOI PMC

Thorpe L.M., Yuzugullu H., Zhao J.J. PI3K in cancer: Divergent roles of isoforms, modes of activation and therapeutic targeting. Nat. Rev. Cancer. 2015;15:7–24. doi: 10.1038/nrc3860. PubMed DOI PMC

Okkenhaug K. Signaling by the phosphoinositide 3-kinase family in immune cells. Annu. Rev. Immunol. 2013;31:675–704. doi: 10.1146/annurev-immunol-032712-095946. PubMed DOI PMC

Sawyer C., Sturge J., Bennett D.C., O’Hare M.J., Allen W.E., Bain J., Jones G.E., Vanhaesebroeck B. Regulation of breast cancer cell chemotaxis by the phosphoinositide 3-kinase p110δ. Cancer Res. 2003;63:1667–1675. PubMed

Koyasu S. The role of PI3K in immune cells. Nat. Immunol. 2003;4:313–319. doi: 10.1038/ni0403-313. PubMed DOI

Ali K., Bilancio A., Thomas M., Pearce W., Gilfillan A.M., Tkaczyk C., Kuehn N., Gray A., Giddings J., Peskett E., et al. Essential role for the p110δ phosphoinositide 3-kinase in the allergic response. Nature. 2004;431:1007–1011. doi: 10.1038/nature02991. PubMed DOI

Lucas C.L., Chandra A., Nejentsev S., Condliffe A.M., Okkenhaug K. PI3Kδ and primary immunodeficiencies. Nat. Rev. Immunol. 2016;16:702–714. doi: 10.1038/nri.2016.93. PubMed DOI PMC

Derenzini E., Rossi A., Trere D. Treating hematological malignancies with drugs inhibiting ribosome biogenesis: When and why. J. Hematol. Oncol. 2018;11:75. doi: 10.1186/s13045-018-0609-1. PubMed DOI PMC

Sander S., Calado D.P., Srinivasan L., Kochert K., Zhang B., Rosolowski M., Rodig S.J., Holzmann K., Stilgenbauer S., Siebert R., et al. Synergy between PI3K signaling and MYC in Burkitt lymphomagenesis. Cancer Cell. 2012;22:167–179. doi: 10.1016/j.ccr.2012.06.012. PubMed DOI PMC

Furman R.R., Sharman J.P., Coutre S.E., Cheson B.D., Pagel J.M., Hillmen P., Barrientos J.C., Zelenetz A.D., Kipps T.J., Flinn I., et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 2014;370:997–1007. doi: 10.1056/NEJMoa1315226. PubMed DOI PMC

Wilson J.B., Bell J.L., Levine A.J. Expression of Epstein-Barr virus nuclear antigen-1 induces B cell neoplasia in transgenic mice. EMBO J. 1996;15:3117–3126. doi: 10.1002/j.1460-2075.1996.tb00674.x. PubMed DOI PMC

Kang M.S., Lu H., Yasui T., Sharpe A., Warren H., Cahir-McFarland E., Bronson R., Hung S.C., Kieff E. Epstein-Barr virus nuclear antigen 1 does not induce lymphoma in transgenic FVB mice. Proc. Natl. Acad. Sci. USA. 2005;102:820–825. doi: 10.1073/pnas.0408774102. PubMed DOI PMC

Actionable cancer vulnerability due to translational arrest, p53 aggregation and ribosome biogenesis stress evoked by the disulfiram metabolite CuET

p53 mRNA Metabolism Links with the DNA Damage Response

Viruses, cancer and non-self recognition

MDM2's dual mRNA binding domains co-ordinate its oncogenic and tumour suppressor activities