Protein production must be strictly controlled at its beginning and end to synthesize a polypeptide that faithfully copies genetic information carried in the encoding mRNA. In contrast to viruses and prokaryotes, the majority of mRNAs in eukaryotes contain only one coding sequence, resulting in production of a single protein. There are, however, many exceptional mRNAs that either carry short open reading frames upstream of the main coding sequence (uORFs) or even contain multiple long ORFs. A wide variety of mechanisms have evolved in microbes and higher eukaryotes to prevent recycling of some or all translational components upon termination of the first translated ORF in such mRNAs and thereby enable subsequent translation of the next uORF or downstream coding sequence. These specialized reinitiation mechanisms are often regulated to couple translation of the downstream ORF to various stimuli. Here we review all known instances of both short uORF-mediated and long ORF-mediated reinitiation and present our current understanding of the underlying molecular mechanisms of these intriguing modes of translational control.

Laboratory of Gene Regulation and Development Eunice Kennedy Shriver National Institute of Child Health and Human Development NIH Bethesda MD 20892 USA

Laboratory of Regulation of Gene Expression Institute of Microbiology ASCR Videnska 1083 Prague 142 20 the Czech Republic

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Abastado JP, Miller PF, Jackson BM et al. . Suppression of ribosomal reinitiation at upstream open reading frames in amino acid-starved cells forms the basis for GCN4 translational control. Mol Cell Biol 1991;11:486–96. PubMed PMC

Adhin MR, van Duin J. Scanning model for translational reinitiation in eubacteria. J Mol Biol 1990;213:811–8. PubMed

Ahmadian G, Randhawa JS, Easton AJ. Expression of the ORF-2 protein of the human respiratory syncytial virus M2 gene is initiated by a ribosomal termination-dependent reinitiation mechanism. EMBO J 2000;19:2681–9. PubMed PMC

Aitken CE, Beznoskova P, Vlckova V et al. . Eukaryotic translation initiation factor 3 plays distinct roles at the mRNA entry and exit channels of the ribosomal preinitiation complex. Elife 2016;5:e20934. PubMed PMC

Algire MA, Maag D, Lorsch JR. Pi release from eIF2, not GTP hydrolysis, is the step controlled by start-site selection during eukaryotic translation initiation. Mol Cell 2005;20:251–62. PubMed

Alisch RS, Garcia-Perez JL, Muotri AR et al. . Unconventional translation of mammalian LINE-1 retrotransposons. Gene Dev 2006;20:210–24. PubMed PMC

Altmann M, Wittmer B, Methot N et al. . The Saccharomyces cerevisiae translation initiation factor Tif3 and its mammalian homologue, eIF-4B, have RNA annealing activity. EMBO J 1995;14:3820–7. PubMed PMC

Amrani N, Ganesan R, Kervestin S et al. . A faux 3΄-UTR promotes aberrant termination and triggers nonsense-mediated mRNA decay. Nature 2004;432:112–8. PubMed

Andreev DE, O’Connor PB, Fahey C et al. . Translation of 5΄ leaders is pervasive in genes resistant to eIF2 repression. Elife 2015a;4:e03971. PubMed PMC

Andreev DE, O’Connor PB, Zhdanov AV et al. . Oxygen and glucose deprivation induces widespread alterations in mRNA translation within 20 minutes. Genome Biol 2015b;16:90. PubMed PMC

Atkins JF, Wills NM, Loughran G et al. . A case for “StopGo”: reprogramming translation to augment codon meaning of GGN by promoting unconventional termination (Stop) after addition of glycine and then allowing continued translation (Go). RNA 2007;13:803–10. PubMed PMC

Aylett CH, Boehringer D, Erzberger JP et al. . Structure of a yeast 40S-eIF1-eIF1A-eIF3-eIF3j initiation complex. Nat Struct Mol Biol 2015;22:269–71. PubMed

Baird TD, Wek RC. Eukaryotic initiation factor 2 phosphorylation and translational control in metabolism. Adv Nutr 2012;3:307–21. PubMed PMC

Barbosa C, Peixeiro I, Romao L. Gene expression regulation by upstream open reading frames and human disease. PLoS Genet 2013;9:e1003529. PubMed PMC

Beznoskova P, Gunisova S, Valasek LS. Rules of UGA-N decoding by near-cognate tRNAs and analysis of readthrough on short uORFs in yeast. RNA 2016;22:456–66. PubMed PMC

Beznosková P, Cuchalová L, Wagner S et al. . Translation initiation factors eIF3 and HCR1 control translation termination and stop codon read-through in yeast cells. PLoS Genet 2013;9:e1003962. PubMed PMC

Bonneville JM, Sanfacon H, Futterer J et al. . Posttranscriptional trans-activation in cauliflower mosaic virus. Cell 1989;59:1135–43. PubMed

Brown JD, Ryan MD. Ribosome “skipping”: “stop-carry on” or “stopGo” translation. In: Atkins JFGesteland RF. eds Recoding: Expansion of Decoding Rules Enriches Gene Expression.. Springer New York, New York, NY, 2010, 101–21.

Buskirk AR, Green R. Ribosome pausing, arrest and rescue in bacteria and eukaryotes. Philos Trans R Soc Lond B Biol Sci 2017;372:20160183. PubMed PMC

Calkhoven CR, Muller C, Leutz A. Translational control of C/EBPa and C/EBPb isoform expression. Gene Dev 2000;14:1920–32. PubMed PMC

Calvo SE, Pagliarini DJ, Mootha VK. Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans. P Natl Acad Sci USA 2009;106:7507–12. PubMed PMC

Chew GL, Pauli A, Schier AF. Conservation of uORF repressiveness and sequence features in mouse, human and zebrafish. Nat Commun 2016;7:11663. PubMed PMC

Cuchalová L, Kouba T, Herrmannová A et al. . The RNA recognition motif of eukaryotic translation initiation factor 3g (eIF3g) is required for resumption of scanning of posttermination ribosomes for reinitiation on GCN4 and together with eIF3i stimulates linear scanning. Mol Cell Biol 2010;30:4671–86. PubMed PMC

des Georges A, Dhote V, Kuhn L et al. . Structure of mammalian eIF3 in the context of the 43S preinitiation complex. Nature 2015;525:491–5. PubMed PMC

Dever TE, Green R. The elongation, termination, and recycling phases of translation in eukaryotes. Cold Spring Harb Perspect Biol 2012;4:a013706. PubMed PMC

Dever TE, Kinzy TG, Pavitt GD. Mechanism and Regulation of Protein Synthesis in Saccharomyces cerevisiae. Genetics 2016;203:65–107. PubMed PMC

Dey S, Baird TD, Zhou D et al. . Both transcriptional regulation and translational control of ATF4 are central to the integrated stress response. J Biol Chem 2010;285:33165–74. PubMed PMC

Donnelly ML, Gani D, Flint M et al. . The cleavage activities of aphthovirus and cardiovirus 2A proteins. J Gen Virol 1997;78(Pt 1):13–21. PubMed

Donnelly ML, Hughes LE, Luke G et al. . The ‘cleavage’ activities of foot-and-mouth disease virus 2A site-directed mutants and naturally occurring ‘2A-like’ sequences. J Gen Virol 2001a;82:1027–41. PubMed

Donnelly ML, Luke G, Mehrotra A et al. . Analysis of the aphthovirus 2A/2B polyprotein ‘cleavage’ mechanism indicates not a proteolytic reaction, but a novel translational effect: a putative ribosomal ‘skip’. J Gen Virol 2001b;82:1013–25. PubMed

Doronina VA, Wu C, de Felipe P et al. . Site-specific release of nascent chains from ribosomes at a sense codon. Mol Cell Biol 2008;28:4227–39. PubMed PMC

Fijalkowska D, Verbruggen S, Ndah E et al. . eIF1 modulates the recognition of suboptimal translation initiation sites and steers gene expression via uORFs. Nucleic Acids Res 2017;45:7997–8013. PubMed PMC

Futterer J, Hohn T. Translation of a polycistronic mRNA in the presence of the cauliflower mosaic virus transactivator protein. EMBO J 1991;10:3887–96. PubMed PMC

Futterer J, Hohn T. Role of an upstream open reading frame in the translation of polycistronic mRNAs in plant cells. Nucleic Acids Res 1992;20:3851–7. PubMed PMC

Gaba A, Wang Z, Krishnamoorthy T et al. . Physical evidence for distinct mechanisms of translational control by upstream open reading frames. EMBO J 2001;20:6453–63. PubMed PMC

Gardner LB. Hypoxic inhibition of nonsense-mediated RNA decay regulates gene expression and the integrated stress response. Mol Cell Biol 2008;28:3729–41. PubMed PMC

Gould PS, Dyer NP, Croft W et al. . Cellular mRNAs access second ORFs using a novel amino acid sequence-dependent coupled translation termination-reinitiation mechanism. RNA 2014;20:373–81. PubMed PMC

Gould PS, Easton AJ. Coupled translation of the respiratory syncytial virus M2 open reading frames requires upstream sequences. J Biol Chem 2005;280:21972–80. PubMed

Gould PS, Easton AJ. Coupled translation of the second open reading frame of M2 mRNA is sequence dependent and differs significantly within the subfamily Pneumovirinae. J Virol 2007;81:8488–96. PubMed PMC

Grant CM, Hinnebusch AG. Effect of sequence context at stop codons on efficiency of reinitiation in GCN4 translational control. Mol Cell Biol 1994;14:606–18. PubMed PMC

Grant CM, Miller PF, Hinnebusch AG. Sequences 5΄ of the first upstream open reading frame in GCN4 mRNA are required for efficient translational reinitiation. Nuc Acids Res 1995;23:3980–8. PubMed PMC

Griffin E, Re A, Hamel N et al. . A link between diabetes and atherosclerosis: glucose regulates expression of CD36 at the level of translation. Nat Med 2001;7:840–6. PubMed

Gunisova S, Beznoskova P, Mohammad MP et al. . In-depth analysis of cis-determinants that either promote or inhibit reinitiation on GCN4 mRNA after translation of its four short uORFs. RNA 2016;22:542–58. PubMed PMC

Gunisova S, Valasek LS. Fail-safe mechanism of GCN4 translational control-uORF2 promotes reinitiation by analogous mechanism to uORF1 and thus secures its key role in GCN4 expression. Nucleic Acids Res 2014;42:5880–93. PubMed PMC

Guo LH, Sun L, Chiba S et al. . Coupled termination/reinitiation for translation of the downstream open reading frame B of the prototypic hypovirus CHV1-EP713. Nucleic Acids Res 2009;37:3645–59. PubMed PMC

Guydosh NR, Green R. Dom34 rescues ribosomes in 3΄ untranslated regions. Cell 2014;156:950–62. PubMed PMC

Habeta M, Luttermann C, Meyers G. Feline calicivirus can tolerate gross changes of its minor capsid protein expression levels induced by changing translation reinitiation frequency or use of a separate VP2-coding mRNA. PLoS One 2014;9:e102254. PubMed PMC

Hashem Y, des Georges A, Dhote V et al. . Structure of the mammalian ribosomal 43S preinitiation complex bound to the scanning factor DHX29. Cell 2013;153:1108–19. PubMed PMC

Hatta M, Kohlmeier CK, Hatta Y et al. . Region required for protein expression from the stop-start pentanucleotide in the M gene of influenza B virus. J Virol 2009;83:5939–42. PubMed PMC

He F, Jacobson A. Nonsense-mediated mRNA decay: degradation of defective transcripts is only part of the story. Annu Rev Genet 2015;49:339–66. PubMed PMC

Heras SR, Thomas MC, Garcia-Canadas M et al. . L1Tc non-LTR retrotransposons from Trypanosoma cruzi contain a functional viral-like self-cleaving 2A sequence in frame with the active proteins they encode. Cell Mol Life Sci 2006;63:1449–60. PubMed PMC

Hinnebusch AG. Translational regulation of GCN4 and the general amino acid control of yeast. Annu Rev Microbiol 2005;59:407–50. PubMed

Hinnebusch AG. The scanning mechanism of eukaryotic translation initiation. Annu Rev Biochem 2014;83:779–812. PubMed

Hinnebusch AG. Structural insights into the mechanism of scanning and start codon recognition in eukaryotic translation initiation. Trends Biochem Sci 2017;42:589–611. PubMed

Hinnebusch AG, Ivanov IP, Sonenberg N. Translational control by 5΄-untranslated regions of eukaryotic mRNAs. Science 2016;352:1413–6. PubMed PMC

Holz MK, Ballif BA, Gygi SP et al. . mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell 2005;123:569–80. PubMed

Horvath CM, Williams MA, Lamb RA. Eukaryotic coupled translation of tandem cistrons: identification of the influenza B virus BM2 polypeptide. EMBO J 1990;9:2639–47. PubMed PMC

Hronova V, Mohammad MP, Wagner S et al. . Does eIF3 promote reinitiation after translation of short upstream ORFs also in mammalian cells? RNA Biol 2017. doi: 10.1080/15476286.15472017.11353863. PubMed PMC

Ingolia NT, Ghaemmaghami S, Newman JRS et al. . Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling. Science 2009;324:218–23. PubMed PMC

Ingolia NT, Lareau LF, Weissman JS. Ribosome profiling of mouse embryonic stem cells reveals the complexity and dynamics of mammalian proteomes. Cell 2011;147:789–802. PubMed PMC

Ivanov IP, Wei J, Caster SZ et al. . Translation initiation from conserved non-AUG codons provides additional layers of regulation and coding capacity. MBio 2017;8:e00844-00817. PubMed PMC

Jackson RJ, Hellen CU, Pestova TV. Termination and post-termination events in eukaryotic translation. Adv Protein Chem Struct Biol 2012;86:45–93. PubMed

Janich P, Arpat AB, Castelo-Szekely V et al. . Ribosome profiling reveals the rhythmic liver translatome and circadian clock regulation by upstream open reading frames. Genome Res 2015;25:1848–59. PubMed PMC

Jennings MD, Kershaw CJ, Adomavicius T et al. . Fail-safe control of translation initiation by dissociation of eIF2alpha phosphorylated ternary complexes. Elife 2017;6:e24542. PubMed PMC

Jennings MD, Pavitt GD. A new function and complexity for protein translation initiation factor eIF2B. Cell Cycle 2014;13:2660–5. PubMed PMC

Ji Z, Song R, Regev A et al. . Many lncRNAs, 5΄UTRs, and pseudogenes are translated and some are likely to express functional proteins. Elife 2015;4:e08890. PubMed PMC

Jivotovskaya A, Valášek L, Hinnebusch AG et al. . Eukaryotic translation initiation factor 3 (eIF3) and eIF2 can promote mRNA binding to 40S subunits independently of eIF4G in yeast. Mol Cell Biol 2006;26:1355–72. PubMed PMC

Khoshnevis S, Gunišová S, Vlčková V et al. . Structural integrity of the PCI domain of eIF3a/TIF32 is required for mRNA recruitment to the 43S pre-initiation complexes. Nucleic Acids Res 2014;42:4123–39. PubMed PMC

Kim BH, Cai X, Vaughn JN et al. . On the functions of the h subunit of eukaryotic initiation factor 3 in late stages of translation initiation. Genome Biol 2007;8:R60. PubMed PMC

Kim TH, Kim BH, Yahalom A et al. . Translational regulation via 5΄ mRNA leader sequences revealed by mutational analysis of the Arabidopsis translation initiation factor subunit eIF3h. Plant Cell 2004;16:3341–56. PubMed PMC

Koditz J, Nesper J, Wottawa M et al. . Oxygen-dependent ATF-4 stability is mediated by the PHD3 oxygen sensor. Blood 2007;110:3610–7. PubMed

Kojima KK, Matsumoto T, Fujiwara H. Eukaryotic translational coupling in UAAUG stop-start codons for the bicistronic RNA translation of the non-long terminal repeat retrotransposon SART1. Mol Cell Biol 2005;25:7675–86. PubMed PMC

Kolupaeva VG, Unbehaun A, Lomakin IB et al. . Binding of eukaryotic initiation factor 3 to ribosomal 40S subunits and its role in ribosomal dissociation and anti-association. RNA 2005;11:470–86. PubMed PMC

Kouba T, Danyi I, Gunišová S et al. . Small ribosomal protein RPS0 stimulates translation initiation by mediating 40S-binding of eIF3 via its direct contact with the eIF3a/TIF32 subunit. PLoS One 2012;7:e40464. PubMed PMC

Kozak M. Effects of intercistronic length on the efficiency of reinitiation by eucaryotic ribosomes. Mol Cell Biol 1987;7:3438–45. PubMed PMC

Kozak M. Structural features in eukaryotic mRNAs that modulate the initiation of translation. J Biol Chem 1991;266:19867–70. PubMed

Kozak M. Constraints on reinitiation of translation in mammals. Nucleic Acids Res 2001;29:5226–32. PubMed PMC

Lawless C, Pearson RD, Selley JN et al. . Upstream sequence elements direct post-transcriptional regulation of gene expression under stress conditions in yeast. BMC Genomics 2009;10:7. PubMed PMC

Li H, Havens WM, Nibert ML et al. . RNA sequence determinants of a coupled termination-reinitiation strategy for downstream open reading frame translation in Helminthosporium victoriae virus 190S and other victoriviruses (Family Totiviridae). J Virol 2011;85:7343–52. PubMed PMC

Llacer JL, Hussain T, Marler L et al. . Conformational differences between open and closed states of the eukaryotic translation initiation complex. Mol Cell 2015;59:399–412. PubMed PMC

Lomakin IB, Stolboushkina EA, Vaidya AT et al. . Crystal structure of the human ribosome in complex with DENR-MCT-1. Cell Rep 2017;20:521–8. PubMed PMC

Loughran G, Howard MT, Firth AE et al. . Avoidance of reporter assay distortions from fused dual reporters. RNA 2017;23:1285–9. PubMed PMC

Lu PD, Harding HP, Ron D. Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response. J Cell Biol 2004;167:27–33. PubMed PMC

Luke G, Escuin H, De Felipe P et al. . 2A to the fore - research, technology and applications. Biotechnol Genet Eng Rev 2010;26:223–60. PubMed

Luke GA, de Felipe P, Lukashev A et al. . Occurrence, function and evolutionary origins of ‘2A-like’ sequences in virus genomes. J Gen Virol 2008;89:1036–42. PubMed PMC

Luo Z, Freitag M, Sachs MS. Translational regulation in response to changes in amino acid availability in Neurospora crassa. Mol Cell Biol 1995;15:5235–45. PubMed PMC

Luttermann C, Meyers G. A bipartite sequence motif induces translation reinitiation in feline calicivirus RNA. J Biol Chem 2007;282:7056–65. PubMed

Luttermann C, Meyers G. The importance of inter- and intramolecular base pairing for translation reinitiation on a eukaryotic bicistronic mRNA. Gene Dev 2009;23:331–44. PubMed PMC

Luttermann C, Meyers G. Two alternative ways of start site selection in human norovirus reinitiation of translation. J Biol Chem 2014;289:11739–54. PubMed PMC

McCormick CJ, Salim O, Lambden PR et al. . Translation termination reinitiation between open reading frame 1 (ORF1) and ORF2 enables capsid expression in a bovine norovirus without the need for production of viral subgenomic RNA. J Virol 2008;82:8917–21. PubMed PMC

Meyers G. Translation of the minor capsid protein of a calicivirus is initiated by a novel termination-dependent reinitiation mechanism. J Biol Chem 2003;278:34051–60. PubMed

Meyers G. Characterization of the sequence element directing translation reinitiation in RNA of the calicivirus rabbit hemorrhagic disease virus. J Virol 2007;81:9623–32. PubMed PMC

Miettinen TP, Bjorklund M. Modified ribosome profiling reveals high abundance of ribosome protected mRNA fragments derived from 3΄ untranslated regions. Nucleic Acids Res 2015;43:1019–34. PubMed PMC

Miller PF, Hinnebusch AG. Sequences that surround the stop codons of upstream open reading frames in GCN4 mRNA determine their distinct functions in translational control. Gene Dev 1989;3:1217–25. PubMed

Mills EW, Wangen J, Green R et al. . Dynamic regulation of a ribosome rescue pathway in erythroid cells and platelets. Cell Rep 2016;17:1–10. PubMed PMC

Mohammad MP, Munzarova Pondelickova V, Zeman J et al. . In vivo evidence that eIF3 stays bound to ribosomes elongating and terminating on short upstream ORFs to promote reinitiation. Nucleic Acids Res 2017;45:2658–74. PubMed PMC

Mueller PP, Hinnebusch AG. Multiple upstream AUG codons mediate translational control of GCN4. Cell 1986;45:201–7. PubMed

Mueller PP, Jackson BM, Miller PF et al. . The first and fourth upstream open reading frames in GCN4 mRNA have similar initiation efficiencies but respond differently in translational control to changes in length and sequence. Mol Cell Biol 1988;8:5439–47. PubMed PMC

Munzarová V, Pánek J, Gunišová S et al. . Translation reinitiation relies on the interaction between eIF3a/TIF32 and progressively folded cis-acting mRNA elements preceding short uORFs. PLoS Genet 2011;7:e1002137. PubMed PMC

Myasnikov AG, Simonetti A, Marzi S et al. . Structure-function insights into prokaryotic and eukaryotic translation initiation. Curr Opin Struct Biol 2009;19:300–9. PubMed

Napthine S, Lever RA, Powell ML et al. . Expression of the VP2 protein of murine norovirus by a translation termination-reinitiation strategy. PLoS One 2009;4:e8390. PubMed PMC

Nishimura T, Wada T, Yamamoto KT et al. . The Arabidopsis STV1 protein, responsible for translation reinitiation, is required for auxin-mediated gynoecium patterning. Plant Cell 2005;17:2940–53. PubMed PMC

Osterman IA, Evfratov SA, Sergiev PV et al. . Comparison of mRNA features affecting translation initiation and reinitiation. Nucleic Acids Res 2013;41:474–86. PubMed PMC

Pakos-Zebrucka K, Koryga I, Mnich K et al. . The integrated stress response. EMBO Rep 2016;17:1374–95. PubMed PMC

Park HS, Browning KS, Hohn T et al. . Eucaryotic initiation factor 4B controls eIF3-mediated ribosomal entry of viral reinitiation factor. EMBO J 2004;23:1381–91. PubMed PMC

Park HS, Himmelbach A, Browning KS et al. . A plant viral “reinitiation” factor interacts with the host translational machinery. Cell 2001;106:723–33. PubMed

Pavlov MY, Watts RE, Tan Z et al. . Slow peptide bond formation by proline and other N-alkylamino acids in translation. P Natl Acad Sci USA 2009;106:50–4. PubMed PMC

Pisarev AV, Hellen CUT, Pestova TV. Recycling of eukaryotic posttermination ribosomal complexes. Cell 2007;131:286–99. PubMed PMC

Pisarev AV, Skabkin MA, Pisareva VP et al. . The role of ABCE1 in eukaryotic posttermination ribosomal recycling. Mol Cell 2010;37:196–210. PubMed PMC

Powell ML. Translational termination-reinitiation in RNA viruses. Biochem Soc Trans 2010;38:1558–64. PubMed

Powell ML, Napthine S, Jackson RJ et al. . Characterization of the termination-reinitiation strategy employed in the expression of influenza B virus BM2 protein. RNA 2008;14:2394–406. PubMed PMC

Powell ML, Leigh KE, Poyry TA et al. . Further characterisation of the translational termination-reinitiation signal of the influenza B virus segment 7 RNA. PLoS One 2011;6:e16822. PubMed PMC

Pöyry TA, Kaminski A, Jackson RJ. What determines whether mammalian ribosomes resume scanning after translation of a short upstream open reading frame? Genes Dev 2004;18:62–75. PubMed PMC

Pöyry TA, Kaminski A, Connell EJ et al. . The mechanism of an exceptional case of reinitiation after translation of a long ORF reveals why such events do not generally occur in mammalian mRNA translation. Gene Dev 2007;21:3149–62. PubMed PMC

Putlyaeva LV, Schwartz AM, Korneev KV et al. . Upstream open reading frames regulate translation of the long isoform of SLAMF1 mRNA that encodes costimulatory receptor CD150. Biochemistry (Mosc) 2014;79:1405–11. PubMed

Rahim G, Araud T, Jaquier-Gubler P et al. . Alternative splicing within the elk-1 5΄ untranslated region serves to modulate initiation events downstream of the highly conserved upstream open reading frame 2. Mol Cell Biol 2012;32:1745–56. PubMed PMC

Roy B, Vaughn JN, Kim B-H et al. . The h subunit of eIF3 promotes reinitiation competence during translation of mRNAs harboring upstream open reading frames. RNA 2010;16:748–61. PubMed PMC

Ryan MD, Drew J. Foot-and-mouth disease virus 2A oligopeptide mediated cleavage of an artificial polyprotein. EMBO J 1994;13:928–33. PubMed PMC

Sattlegger E, Hinnebusch AG, Barthelmess IB. cpc-3, the Neurospora crassa homologue of yeast GCN2, encodes a polypeptide with juxtaposed eIF2a kinase and histidyl-tRNA synthetase-related domains required for general amino acid control. J Biol Chem 1998;273:20404–16. PubMed

Sen ND, Zhou F, Ingolia NT et al. . Genome-wide analysis of translational efficiency reveals distinct but overlapping functions of yeast DEAD-box RNA helicases Ded1 and eIF4A. Genome Res 2015;25:1196–205. PubMed PMC

Shoemaker CJ, Green R. Kinetic analysis reveals the ordered coupling of translation termination and ribosome recycling in yeast. P Natl Acad Sci USA 2011;108:E1392–8. PubMed PMC

Schepetilnikov M, Dimitrova M, Mancera-Martinez E et al. . TOR and S6K1 promote translation reinitiation of uORF-containing mRNAs via phosphorylation of eIF3h. EMBO J 2013;32:1087–102. PubMed PMC

Schepetilnikov M, Kobayashi K, Geldreich A et al. . Viral factor TAV recruits TOR/S6K1 signalling to activate reinitiation after long ORF translation. EMBO J 2011;30:1343–56. PubMed PMC

Schleich S, Acevedo JM, Clemm von Hohenberg K et al. . Identification of transcripts with short stuORFs as targets for DENR*MCTS1-dependent translation in human cells. Sci Rep 2017;7:3722. PubMed PMC

Schleich S, Strassburger K, Janiesch PC et al. . DENR-MCT-1 promotes translation re-initiation downstream of uORFs to control tissue growth. Nature 2014;512:208–12. PubMed PMC

Sidrauski C, McGeachy AM, Ingolia NT et al. . The small molecule ISRIB reverses the effects of eIF2alpha phosphorylation on translation and stress granule assembly. Elife 2015;4:e05033. PubMed PMC

Skabkin MA, Skabkina OV, Dhote V et al. . Activities of Ligatin and MCT-1/DENR in eukaryotic translation initiation and ribosomal recycling. Gene Dev 2010;24:1787–801. PubMed PMC

Skabkin MA, Skabkina OV, Hellen CU et al. . Reinitiation and other unconventional posttermination events during eukaryotic translation. Mol Cell 2013;51:249–64. PubMed PMC

Starck SR, Tsai JC, Chen K et al. . Translation from the 5΄ untranslated region shapes the integrated stress response. Science 2016;351:aad3867. PubMed PMC

Sundaram A, Grant CM. A single inhibitory upstream open reading frame (uORF) is sufficient to regulate Candida albicans GCN4 translation in response to amino acid starvation conditions. RNA 2014;20:559–67. PubMed PMC

Svitkin YV, Agol VI. Translational barrier in central region of encephalomyocarditis virus genome. Modulation by elongation factor 2 (eEF-2). Eur J Biochem 1983;133:145–54. PubMed

Szabo G, Katarova Z, Greenspan R. Distinct protein forms are produced from alternatively spliced bicistronic glutamic acid decarboxylase mRNAs during development. Mol Cell Biol 1994;14:7535–45. PubMed PMC

Szamecz B, Rutkai E, Cuchalova L et al. . eIF3a cooperates with sequences 5΄ of uORF1 to promote resumption of scanning by post-termination ribosomes for reinitiation on GCN4 mRNA. Gene Dev 2008;22:2414–25. PubMed PMC

Tanaka M, Sotta N, Yamazumi Y et al. . The minimum open reading frame, AUG-stop, induces boron-dependent ribosome stalling and mRNA degradation. Plant Cell 2016;28:2830–49. PubMed PMC

Thiebeauld O, Schepetilnikov M, Park HS et al. . A new plant protein interacts with eIF3 and 60S to enhance virus-activated translation re-initiation. EMBO J 2009;28:3171–84. PubMed PMC

Thompson SR. Tricks an IRES uses to enslave ribosomes. Trends Microbiol 2012;20:558–66. PubMed PMC

Valášek L, Mathew A, Shin BS et al. . The yeast eIF3 subunits TIF32/a and NIP1/c and eIF5 make critical connections with the 40S ribosome in vivo. Genes Dev 2003;17:786–99. PubMed PMC

Valášek LS. ΄Ribozoomin’—translation initiation from the perspective of the ribosome-bound eukaryotic initiation factors (eIFs). Curr Protein Pept Sci 2012;13:305–30. PubMed PMC

Valasek LS, Zeman J, Wagner S et al. . Embraced by eIF3: structural and functional insights into the roles of eIF3 across the translation cycle. Nucleic Acids Res 2017;45:10948–68. PubMed PMC

Vattem KM, Wek RC. Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. P Natl Acad Sci USA 2004;101:11269–74. PubMed PMC

von Arnim AG, Jia Q, Vaughn JN. Regulation of plant translation by upstream open reading frames. Plant Sci 2014;214:1–12. PubMed

Weisser M, Schafer T, Leibundgut M et al. . Structural and functional insights into human re-initiation complexes. Mol Cell 2017;67:447–56e447. PubMed

Wethmar K. The regulatory potential of upstream open reading frames in eukaryotic gene expression. Wiley Interdiscip Rev RNA 2014;5:765–78. PubMed

Wohlgemuth WA, Safonova O, Engelhardt M et al. . Improvement of the quality of life concerning the health of patients with peripheral arterial disease (PAD) after successful bypass surgery. Vasa 2008;37:338–44. PubMed

Yamamoto H, Wittek D, Gupta R et al. . 70S-scanning initiation is a novel and frequent initiation mode of ribosomal translation in bacteria. P Natl Acad Sci USA 2016;113:E1180–9. PubMed PMC

Young DJ, Guydosh NR, Zhang F et al. . Rli1/ABCE1 recycles terminating ribosomes and controls translation reinitiation in 3΄UTRs in vivo. Cell 2015;162:872–84. PubMed PMC

Zhou F, Roy B, Dunlap JR et al. . Translational control of Arabidopsis meristem stability and organogenesis by the eukaryotic translation factor eIF3h. PLoS One 2014;9:e95396. PubMed PMC

Zhou F, Roy B, von Arnim AG. Translation reinitiation and development are compromised in similar ways by mutations in translation initiation factor eIF3h and the ribosomal protein RPL24. BMC Plant Biol 2010;10:193. PubMed PMC

Zinoviev A, Hellen CU, Pestova TV. Multiple mechanisms of reinitiation on bicistronic calicivirus mRNAs. Mol Cell 2015;57:1059–73. PubMed PMC

Guidelines for minimal reporting requirements, design and interpretation of experiments involving the use of eukaryotic dual gene expression reporters (MINDR)

Differential effects of 40S ribosome recycling factors on reinitiation at regulatory uORFs in GCN4 mRNA are not dictated by their roles in bulk 40S recycling

Stem-loop-induced ribosome queuing in the uORF2/ATF4 overlap fine-tunes stress-induced human ATF4 translational control

Impacts of yeast Tma20/MCTS1, Tma22/DENR and Tma64/eIF2D on translation reinitiation and ribosome recycling

Quantitative analysis of redox proteome reveals oxidation-sensitive protein thiols acting in fundamental processes of developmental hematopoiesis

eIF4G is retained on ribosomes elongating and terminating on short upstream ORFs to control reinitiation in yeast

Selective Translation Complex Profiling Reveals Staged Initiation and Co-translational Assembly of Initiation Factor Complexes

Binding of eIF3 in complex with eIF5 and eIF1 to the 40S ribosomal subunit is accompanied by dramatic structural changes