Cap-dependent, scanning-free translation initiation mechanisms.

Eukaryotic translation initiation is an intricate and multi-step process that includes 43S Pre-Initiation Complex (PIC) assembly, attachment of the PIC to the mRNA, scanning, start codon selection and 60S subunit joining. Translation initiation of most mRNAs involves recognition of a 5'end m7G cap and ribosomal scanning in which the 5' UTR is checked for complementarity with the AUG. There is however an increasing number of mRNAs directing translation initiation that deviate from the predominant mechanism. In this review we summarize the canonical translation initiation process and describe non-canonical mechanisms that are cap-dependent but operate without scanning. In particular we focus on several examples of translation initiation driven either by mRNAs with extremely short 5' leaders or by highly complex 5' UTRs that promote ribosome shunting.

[1]  R. Parker,et al.  The DEAD-box protein Ded1 modulates translation by the formation and resolution of an eIF4F-mRNA complex. , 2011, Molecular cell.

[2]  C. Fraser,et al.  Duplex unwinding and ATPase activities of the DEAD-box helicase eIF4A are coupled by eIF4G and eIF4B. , 2011, Journal of molecular biology.

[3]  E. Wagner,et al.  Metabolism and regulation of canonical histone mRNAs: life without a poly(A) tail , 2008, Nature Reviews Genetics.

[4]  T. Pestova,et al.  The roles of individual eukaryotic translation initiation factors in ribosomal scanning and initiation codon selection. , 2002, Genes & development.

[5]  M. Kozak,et al.  Regulation of translation via mRNA structure in prokaryotes and eukaryotes. , 2005, Gene.

[6]  M. Kozak,et al.  Pushing the limits of the scanning mechanism for initiation of translation , 2002, Gene.

[7]  Gaochao Zhou,et al.  AMPK: an emerging drug target for diabetes and the metabolic syndrome. , 2009, Cell metabolism.

[8]  A. Marintchev.  Roles of helicases in translation initiation: a mechanistic view. , 2013, Biochimica et biophysica acta.

[9]  M. Moore,et al.  Interactions between eIF4AI and its accessory factors eIF4B and eIF4H. , 2008, RNA.

[10]  G. Wagner,et al.  Structural basis for the enhancement of eIF4A helicase activity by eIF4G. , 2005, Genes & development.

[11]  B. Viollet,et al.  Translational tolerance of mitochondrial genes to metabolic energy stress involves TISU and eIF1-eIF4GI cooperation in start codon selection. , 2015, Cell metabolism.

[12]  Miguel A. Andrade-Navarro,et al.  uORFdb—a comprehensive literature database on eukaryotic uORF biology , 2013, Nucleic Acids Res..

[13]  Graziano Pesole,et al.  uAUG and uORFs in human and rodent 5'untranslated mRNAs. , 2005, Gene.

[14]  R. Dikstein.  Transcription and translation in a package deal: the TISU paradigm. , 2012, Gene.

[15]  A. Komar,et al.  Translation Initiation on Mammalian mRNAs with Structured 5′UTRs Requires DExH-Box Protein DHX29 , 2008, Cell.

[16]  R. Jackson.  The current status of vertebrate cellular mRNA IRESs. , 2013, Cold Spring Harbor perspectives in biology.

[17]  Ching C. Wang,et al.  Capped mRNA with a Single Nucleotide Leader Is Optimally Translated in a Primitive Eukaryote, Giardia lamblia* , 2004, Journal of Biological Chemistry.

[18]  W. Merrick,et al.  Modulation of the Helicase Activity of eIF4A by eIF4B, eIF4H, and eIF4F* , 2001, The Journal of Biological Chemistry.

[19]  Aaron K. LeFebvre,et al.  Translation Initiation Factor eIF4G-1 Binds to eIF3 through the eIF3e Subunit* , 2006, Journal of Biological Chemistry.

[20]  Xue-Qing Wang,et al.  5'-untranslated regions with multiple upstream AUG codons can support low-level translation via leaky scanning and reinitiation. , 2004, Nucleic acids research.

[21]  Mark Muldoon,et al.  Dynamics and processivity of 40S ribosome scanning on mRNA in yeast , 2004, Molecular microbiology.

[22]  E. Harris,et al.  Dengue Virus Utilizes a Novel Strategy for Translation Initiation When Cap-Dependent Translation Is Inhibited , 2006, Journal of Virology.

[23]  W. Merrick,et al.  Intrinsic RNA Binding by the Eukaryotic Initiation Factor 4F Depends on a Minimal RNA Length but Not on the m7G Cap* , 2009, The Journal of Biological Chemistry.

[24]  M. Kozak,et al.  A short leader sequence impairs the fidelity of initiation by eukaryotic ribosomes. , 1991, Gene expression.

[25]  W. Marzluff,et al.  The histone 3'-terminal stem-loop is necessary for translation in Chinese hamster ovary cells. , 1996, Nucleic acids research.

[26]  Christoph Handschin,et al.  Metabolic control through the PGC-1 family of transcription coactivators. , 2005, Cell metabolism.

[27]  C. Hellen,et al.  Specific functional interactions of nucleotides at key -3 and +4 positions flanking the initiation codon with components of the mammalian 48S translation initiation complex. , 2006, Genes & development.

[28]  G. Wagner,et al.  Translation initiation: structures, mechanisms and evolution , 2004, Quarterly Reviews of Biophysics.

[29]  Johannes Fütterer,et al.  Nonlinear ribosome migration on cauliflower mosaic virus 35S RNA , 1993, Cell.

[30]  R. Jackson,et al.  The mechanism of eukaryotic translation initiation and principles of its regulation , 2010, Nature Reviews Molecular Cell Biology.

[31]  M. Kozak.  Effects of long 5' leader sequences on initiation by eukaryotic ribosomes in vitro. , 1991, Gene expression.

[32]  M. Shago,et al.  Translation of the Saccharomyces cerevisiae tcm1 gene in the absence of a 5'-untranslated leader. , 1990, Nucleic acids research.

[33]  Edna Schechtman,et al.  Co-occurrence of transcription and translation gene regulatory features underlies coordinated mRNA and protein synthesis , 2014, BMC Genomics.

[34]  Sarah E. Walker,et al.  Multiple elements in the eIF4G1 N‐terminus promote assembly of eIF4G1•PABP mRNPs in vivo , 2011, The EMBO journal.

[35]  R. Hull,et al.  Position-dependent ATT initiation during plant pararetrovirus rice tungro bacilliform virus translation , 1996, Journal of virology.

[36]  M. Tarnopolsky,et al.  AMP-activated protein kinase (AMPK) β1β2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise , 2011, Proceedings of the National Academy of Sciences.

[37]  W. Winder,et al.  Activation of AMP-activated protein kinase increases mitochondrial enzymes in skeletal muscle. , 2000, Journal of applied physiology.

[38]  B. Spiegelman,et al.  AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. , 2007, Proceedings of the National Academy of Sciences of the United States of America.

[39]  N. Gray,et al.  The stem-loop binding protein stimulates histone translation at an early step in the initiation pathway. , 2005, RNA.

[40]  B. Spiegelman,et al.  AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α , 2007, Proceedings of the National Academy of Sciences.

[41]  A. Hinnebusch,et al.  Regulation of Translation Initiation in Eukaryotes: Mechanisms and Biological Targets , 2009, Cell.

[42]  N. Sonenberg,et al.  Topology and Regulation of the Human eIF4A/4G/4H Helicase Complex in Translation Initiation , 2009, Cell.

[43]  G. Edelman,et al.  Differential utilization of upstream AUGs in the beta-secretase mRNA suggests that a shunting mechanism regulates translation. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[44]  G. Pesole,et al.  rRNA-like sequences in human mRNAs. , 2002, Applied bioinformatics.

[45]  G. Edelman,et al.  Ribosomal shunting mediated by a translational enhancer element that base pairs to 18S rRNA. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[46]  G. Eriani,et al.  Cap-assisted internal initiation of translation of histone H4. , 2011, Molecular cell.

[47]  R. Chuang,et al.  Requirement of the DEAD-Box Protein Ded1p for Messenger RNA Translation , 1997, Science.

[48]  Nancy Y. Villa,et al.  Human Eukaryotic Initiation Factor 4G (eIF4G) Protein Binds to eIF3c, -d, and -e to Promote mRNA Recruitment to the Ribosome* , 2013, The Journal of Biological Chemistry.

[49]  D. Bolster,et al.  AMP-activated Protein Kinase Suppresses Protein Synthesis in Rat Skeletal Muscle through Down-regulated Mammalian Target of Rapamycin (mTOR) Signaling* , 2002, The Journal of Biological Chemistry.

[50]  N. Sonenberg,et al.  Unique translation initiation of mRNAs-containing TISU element , 2011, Nucleic acids research.

[51]  P. Dubbelhuis,et al.  Hepatic amino acid‐dependent signaling is under the control of AMP‐dependent protein kinase , 2002, FEBS letters.

[52]  D. Kolakofsky,et al.  Sendai Virus Y Proteins Are Initiated by a Ribosomal Shunt , 1998, Molecular and Cellular Biology.

[53]  N. Sonenberg,et al.  Requirement of RNA Binding of Mammalian Eukaryotic Translation Initiation Factor 4GI (eIF4GI) for Efficient Interaction of eIF4E with the mRNA Cap , 2008, Molecular and Cellular Biology.

[54]  Reconciling contradictory reports regarding translation of BACE1 mRNA: initiation mechanism is altered by different expression systems , 2009, RNA biology.

[55]  A. Cigan,et al.  tRNAi(met) functions in directing the scanning ribosome to the start site of translation. , 1988, Science.

[56]  S. Thompson.  Tricks an IRES uses to enslave ribosomes. , 2012, Trends in microbiology.

[57]  J. Auwerx,et al.  Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. , 2010, Cell metabolism.

[58]  D. Bolster,et al.  Repression of protein synthesis and mTOR signaling in rat liver mediated by the AMPK activator aminoimidazole carboxamide ribonucleoside. , 2005, American journal of physiology. Endocrinology and metabolism.

[59]  M. Leippe,et al.  Unusual gene organization in the protozoan parasite Entamoeba histolytica. , 1993, DNA and cell biology.

[60]  Bin Li,et al.  The Yeast Eukaryotic Initiation Factor 4G (eIF4G) HEAT Domain Interacts with eIF1 and eIF5 and Is Involved in Stringent AUG Selection , 2003, Molecular and Cellular Biology.

[61]  Christos G. Gkogkas,et al.  mRNA helicases: the tacticians of translational control , 2011, Nature Reviews Molecular Cell Biology.

[62]  Marija Mihailovich,et al.  Translational regulation of BACE-1 expression in neuronal and non-neuronal cells. , 2004, Nucleic acids research.

[63]  V. Mootha,et al.  Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans , 2009, Proceedings of the National Academy of Sciences.

[64]  G. Wagner,et al.  Position of eukaryotic initiation factor eIF1 on the 40S ribosomal subunit determined by directed hydroxyl radical probing. , 2003, Genes & development.

[65]  L. Bertrand,et al.  Control of p70 ribosomal protein S6 kinase and acetyl-CoA carboxylase by AMP-activated protein kinase and protein phosphatases in isolated hepatocytes. , 2002, European journal of biochemistry.

[66]  M. Hentze,et al.  Complex translational regulation of BACE1 involves upstream AUGs and stimulatory elements within the 5′ untranslated region , 2007, Nucleic acids research.

[67]  Jon R Lorsch,et al.  A mechanistic overview of translation initiation in eukaryotes , 2012, Nature Structural &Molecular Biology.

[68]  R. W. Finley,et al.  Trichomonas vaginalis: analysis of a heat-inducible member of the cytosolic heat-shock-protein 70 multigene family , 2000, Parasitology Research.

[69]  A. Yueh,et al.  Translation by ribosome shunting on adenovirus and hsp70 mRNAs facilitated by complementarity to 18S rRNA. , 2000, Genes & development.

[70]  V. Prassolov,et al.  Distinctive Properties of the 5′-Untranslated Region of Human Hsp70 mRNA* , 2003, Journal of Biological Chemistry.

[71]  Alan G Hinnebusch,et al.  The scanning mechanism of eukaryotic translation initiation. , 2014, Annual review of biochemistry.

[72]  C. Gualerzi,et al.  Selective stimulation of translation of leaderless mRNA by initiation factor 2: evolutionary implications for translation , 2000, The EMBO journal.

[73]  Miss A.O. Penney.  (b) , 1974, The New Yale Book of Quotations.

[74]  R. Vale,et al.  Circularization of mRNA by eukaryotic translation initiation factors. , 1998, Molecular cell.

[75]  R. Dikstein,et al.  A Translation Initiation Element Specific to mRNAs with Very Short 5′UTR that Also Regulates Transcription , 2008, PloS one.

[76]  R. Lloyd,et al.  Translation of cIAP2 mRNA Is Mediated Exclusively by a Stress-Modulated Ribosome Shunt , 2008, Molecular and Cellular Biology.

[77]  W. Marzluff,et al.  The Stem-Loop Binding Protein Is Required for Efficient Translation of Histone mRNA In Vivo and In Vitro , 2002, Molecular and Cellular Biology.

[78]  E. Wagner,et al.  SLIP1, a Factor Required for Activation of Histone mRNA Translation by the Stem-Loop Binding Protein , 2007, Molecular and Cellular Biology.

[79]  A. Komar,et al.  A new framework for understanding IRES-mediated translation. , 2012, Gene.