Please Do Not Recycle! Translation Reinitiation in Microbes and Higher Eukaryotes

Overview

Journal FEMS Microbiol Rev

Publisher Oxford University Press

Specialty Microbiology

Date 2017 Dec 28

PMID 29281028

Citations 49

Authors

Stanislava Gunisova

Vladislava Hronova

Mahabub Pasha Mohammad

Alan G Hinnebusch

Leos Shivaya Valasek

Affiliations

Soon will be listed here.

Abstract

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.

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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.

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

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References

Mohammad M, Munzarova Pondelickova V, Zeman J, Gunisova S, Valasek L . In vivo evidence that eIF3 stays bound to ribosomes elongating and terminating on short upstream ORFs to promote reinitiation. Nucleic Acids Res. 2017; 45(5):2658-2674. PMC: 5389480. DOI: 10.1093/nar/gkx049. View

Gardner L . Hypoxic inhibition of nonsense-mediated RNA decay regulates gene expression and the integrated stress response. Mol Cell Biol. 2008; 28(11):3729-41. PMC: 2423288. DOI: 10.1128/MCB.02284-07. View

Gaba A, Wang Z, Krishnamoorthy T, Hinnebusch A, Sachs M . Physical evidence for distinct mechanisms of translational control by upstream open reading frames. EMBO J. 2001; 20(22):6453-63. PMC: 125715. DOI: 10.1093/emboj/20.22.6453. View

Mueller P, Hinnebusch A . Multiple upstream AUG codons mediate translational control of GCN4. Cell. 1986; 45(2):201-7. DOI: 10.1016/0092-8674(86)90384-3. View

Heras S, Thomas M, Garcia-Canadas M, de Felipe P, Garcia-Perez J, Ryan M . 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(12):1449-60. PMC: 11136212. DOI: 10.1007/s00018-006-6038-2. View

Hinnebusch A . The scanning mechanism of eukaryotic translation initiation. Annu Rev Biochem. 2014; 83:779-812. DOI: 10.1146/annurev-biochem-060713-035802. View

Kouba T, Danyi I, Gunisova S, Munzarova V, Vlckova V, Cuchalova L . 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(7):e40464. PMC: 3390373. DOI: 10.1371/journal.pone.0040464. View

Thompson S . Tricks an IRES uses to enslave ribosomes. Trends Microbiol. 2012; 20(11):558-66. PMC: 3479354. DOI: 10.1016/j.tim.2012.08.002. View

Gould P, Easton A . Coupled translation of the respiratory syncytial virus M2 open reading frames requires upstream sequences. J Biol Chem. 2005; 280(23):21972-80. DOI: 10.1074/jbc.M502276200. View

10.

Aylett C, Boehringer D, Erzberger J, Schaefer T, Ban N . Structure of a yeast 40S-eIF1-eIF1A-eIF3-eIF3j initiation complex. Nat Struct Mol Biol. 2015; 22(3):269-71. DOI: 10.1038/nsmb.2963. View

11.

Ryan M, Drew J . Foot-and-mouth disease virus 2A oligopeptide mediated cleavage of an artificial polyprotein. EMBO J. 1994; 13(4):928-33. PMC: 394894. DOI: 10.1002/j.1460-2075.1994.tb06337.x. View

12.

Myasnikov A, Simonetti A, Marzi S, Klaholz B . Structure-function insights into prokaryotic and eukaryotic translation initiation. Curr Opin Struct Biol. 2009; 19(3):300-9. DOI: 10.1016/j.sbi.2009.04.010. View

13.

Ingolia N, Ghaemmaghami S, Newman J, Weissman J . Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling. Science. 2009; 324(5924):218-23. PMC: 2746483. DOI: 10.1126/science.1168978. View

14.

Valasek L, Zeman J, Wagner S, Beznoskova P, Pavlikova Z, Mohammad M . Embraced by eIF3: structural and functional insights into the roles of eIF3 across the translation cycle. Nucleic Acids Res. 2017; 45(19):10948-10968. PMC: 5737393. DOI: 10.1093/nar/gkx805. View

15.

Grant C, Hinnebusch A . Effect of sequence context at stop codons on efficiency of reinitiation in GCN4 translational control. Mol Cell Biol. 1994; 14(1):606-18. PMC: 358410. DOI: 10.1128/mcb.14.1.606-618.1994. View

16.

Luttermann C, Meyers G . The importance of inter- and intramolecular base pairing for translation reinitiation on a eukaryotic bicistronic mRNA. Genes Dev. 2009; 23(3):331-44. PMC: 2648545. DOI: 10.1101/gad.507609. View

17.

Hronova V, Mohammad M, Wagner S, Panek J, Gunisova S, Zeman J . Does eIF3 promote reinitiation after translation of short upstream ORFs also in mammalian cells?. RNA Biol. 2017; 14(12):1660-1667. PMC: 5731805. DOI: 10.1080/15476286.2017.1353863. View

18.

Wethmar K . The regulatory potential of upstream open reading frames in eukaryotic gene expression. Wiley Interdiscip Rev RNA. 2014; 5(6):765-78. DOI: 10.1002/wrna.1245. View

19.

Holz M, Ballif B, Gygi S, Blenis J . mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell. 2005; 123(4):569-80. DOI: 10.1016/j.cell.2005.10.024. View

20.

Gould P, Dyer N, Croft W, Ott S, Easton A . Cellular mRNAs access second ORFs using a novel amino acid sequence-dependent coupled translation termination-reinitiation mechanism. RNA. 2014; 20(3):373-81. PMC: 3923131. DOI: 10.1261/rna.041574.113. View