The regulatory potential of upstream open reading frames in eukaryotic gene expression

Upstream open reading frames (uORFs) are prevalent cis‐regulatory sequence elements in the transcript leader sequences (TLSs) of eukaryotic mRNAs. The majority of uORFs is considered to repress downstream translation by the consumption of functional pre‐initiation complexes or by inhibiting unrestrained progression of the ribosome. Under distinct conditions, specific uORF properties or sequential arrangements of uORFs can oppositely confer enhanced translation of the main coding sequence, designating uORFs as versatile modifiers of gene expression. Ribosome profiling and proteomic studies demonstrated widespread translational activity at AUG‐ and non‐AUG‐initiated uORFs in eukaryotic transcriptomes from yeast to human and several reports linked defective uORF‐mediated translational control to the development of human diseases. This review summarizes the structural features affecting uORF‐mediated translational control in eukaryotes and describes the highly divergent mechanisms of uORF regulation that result in repression or induction of downstream protein translation. WIREs RNA 2014, 5:765–768. doi: 10.1002/wrna.1245

[1]  G. Mize,et al.  Role of two upstream open reading frames in the translational control of oncogene mdm2 , 1999, Oncogene.

[2]  M. Kozak,et al.  At least six nucleotides preceding the AUG initiator codon enhance translation in mammalian cells. , 1987, Journal of molecular biology.

[3]  B. Ouyang,et al.  Differential expression of estrogen receptor beta isoforms in prostate cancer through interplay between transcriptional and translational regulation , 2013, Molecular and Cellular Endocrinology.

[4]  A. Hinnebusch.  Evidence for translational regulation of the activator of general amino acid control in yeast. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Mark L Crowe,et al.  Evidence for conservation and selection of upstream open reading frames suggests probable encoding of bioactive peptides , 2006, BMC Genomics.

[6]  B. M. Jackson,et al.  Suppression of ribosomal reinitiation at upstream open reading frames in amino acid-starved cells forms the basis for GCN4 translational control , 1991, Molecular and cellular biology.

[7]  Yang Liu,et al.  Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis , 2009, Nature Genetics.

[8]  D. Morris,et al.  Polyamine regulation of ribosome pausing at the upstream open reading frame of S-adenosylmethionine decarboxylase. , 2001, The Journal of biological chemistry.

[9]  D. Rigal,et al.  Upstream open reading frames regulate translation of Mona/Gads adapter mRNA in the megakaryocytic lineage , 2002, Platelets.

[10]  M. Schapira,et al.  Regulated translation initiation controls stress-induced gene expression in mammalian cells. , 2000, Molecular cell.

[11]  Ton Schoenmaker,et al.  Transcription factor C/EBPβ isoform ratio regulates osteoclastogenesis through MafB , 2009, The EMBO journal.

[12]  Francisco Martinez-Murillo,et al.  Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise , 2004, Nature Genetics.

[13]  V. Speirs,et al.  Differential regulation of oestrogen receptor β isoforms by 5′ untranslated regions in cancer , 2009, Journal of cellular and molecular medicine.

[14]  Igor B. Rogozin,et al.  Evolutionary conservation suggests a regulatory function of AUG triplets in 5′-UTRs of eukaryotic genes , 2005, Nucleic acids research.

[15]  G. Mize,et al.  The Two Upstream Open Reading Frames of Oncogene mdm2 Have Different Translational Regulatory Properties* , 2003, Journal of Biological Chemistry.

[16]  Richard J Jackson,et al.  Termination and post-termination events in eukaryotic translation. , 2012, Advances in protein chemistry and structural biology.

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

[18]  M. Sachs,et al.  Evolutionary changes in the fungal carbamoyl-phosphate synthetase small subunit gene and its associated upstream open reading frame. , 2007, Fungal genetics and biology : FG & B.

[19]  Matthew D. Disney,et al.  Identifying the Preferred RNA Motifs and Chemotypes that Interact by Probing Millions of Combinations , 2012, Nature Communications.

[20]  B. Shen,et al.  Global mapping of translation initiation sites in mammalian cells at single-nucleotide resolution , 2012, Proceedings of the National Academy of Sciences.

[21]  F. Gannon,et al.  Upstream Open Reading Frames Regulate the Translation of the Multiple mRNA Variants of the Estrogen Receptor α* , 2002, The Journal of Biological Chemistry.

[22]  Heidi Dvinge,et al.  Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells. , 2008, Cancer cell.

[23]  V. Gladyshev,et al.  Genome-wide ribosome profiling reveals complex translational regulation in response to oxidative stress , 2012, Proceedings of the National Academy of Sciences.

[24]  Donghui Zhou,et al.  Phosphorylation of eIF2 Directs ATF5 Translational Control in Response to Diverse Stress Conditions* , 2008, Journal of Biological Chemistry.

[25]  B. G. Luukkonen,et al.  Efficiency of reinitiation of translation on human immunodeficiency virus type 1 mRNAs is determined by the length of the upstream open reading frame and by intercistronic distance , 1995, Journal of virology.

[26]  T. Preiss,et al.  Termination and Peptide Release at the Upstream Open Reading Frame Are Required for Downstream Translation on Synthetic Shunt-Competent mRNA Leaders , 2000, Molecular and Cellular Biology.

[27]  Z. Chen,et al.  Glutamine stimulates translation of uncoupling protein 2mRNA , 2007, Cellular and Molecular Life Sciences.

[28]  Timothy McCaffrey,et al.  A link between diabetes and atherosclerosis: Glucose regulates expression of CD36 at the level of translation , 2001, Nature Medicine.

[29]  M. Kozak.  Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes , 1986, Cell.

[30]  Josef Pánek,et al.  Translation Reinitiation Relies on the Interaction between eIF3a/TIF32 and Progressively Folded cis-Acting mRNA Elements Preceding Short uORFs , 2011, PLoS genetics.

[31]  Susana Rivas,et al.  Trans-regulation of the expression of the transcription factor MtHAP2-1 by a uORF controls root nodule development. , 2008, Genes & development.

[32]  M. Kozak,et al.  Circumstances and mechanisms of inhibition of translation by secondary structure in eucaryotic mRNAs , 1989, Molecular and cellular biology.

[33]  A. Geballe,et al.  Inhibition of nascent-peptide release at translation termination , 1996, Molecular and cellular biology.

[34]  C. Rodrigues-Pousada,et al.  Post‐termination ribosome interactions with the 5′UTR modulate yeast mRNA stability , 1999, The EMBO journal.

[35]  Sjef Smeekens,et al.  A Conserved Upstream Open Reading Frame Mediates Sucrose-Induced Repression of Translation , 2004, The Plant Cell Online.

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

[37]  R. Wek,et al.  Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[38]  A. Hinnebusch,et al.  An upstream ORF with non-AUG start codon is translated in vivo but dispensable for translational control of GCN4 mRNA , 2011, Nucleic acids research.

[39]  F. Urano,et al.  Inhibition of CHOP translation by a peptide encoded by an open reading frame localized in the chop 5'UTR. , 2001, Nucleic acids research.

[40]  Alessandro Quattrone,et al.  A Novel Mutation in the Upstream Open Reading Frame of the CDKN1B Gene Causes a MEN4 Phenotype , 2013, PLoS genetics.

[41]  B. Kobilka,et al.  The peptide product of a 5' leader cistron in the beta 2 adrenergic receptor mRNA inhibits receptor synthesis. , 1994, The Journal of biological chemistry.

[42]  Ya-Yun Cheng,et al.  Differential regulation of CHOP translation by phosphorylated eIF4E under stress conditions , 2009, Nucleic acids research.

[43]  A. Hinnebusch,et al.  Sequences that surround the stop codons of upstream open reading frames in GCN4 mRNA determine their distinct functions in translational control. , 1989, Genes & development.

[44]  A. Komar,et al.  The Zipper Model of Translational Control A Small Upstream ORF Is the Switch that Controls Structural Remodeling of an mRNA Leader , 2003, Cell.

[45]  Ross Smith,et al.  uPEPperoni: An online tool for upstream open reading frame location and analysis of transcript conservation , 2014, BMC Bioinformatics.

[46]  J. Rinn,et al.  Peptidomic discovery of short open reading frame-encoded peptides in human cells , 2012, Nature chemical biology.

[47]  J. Hill,et al.  Cell-specific translational regulation of S-adenosylmethionine decarboxylase mRNA. Dependence on translation and coding capacity of the cis-acting upstream open reading frame. , 1993, The Journal of biological chemistry.

[48]  M. Kozak,et al.  Constraints on reinitiation of translation in mammals. , 2001, Nucleic acids research.

[49]  M. Kozak,et al.  Downstream secondary structure facilitates recognition of initiator codons by eukaryotic ribosomes. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

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

[51]  A. Hinnebusch.  Translational regulation of GCN4 and the general amino acid control of yeast. , 2005, Annual review of microbiology.

[52]  A. Hinnebusch,et al.  Effect of sequence context at stop codons on efficiency of reinitiation in GCN4 translational control , 1994, Molecular and cellular biology.

[53]  Tetsuya Sakurai,et al.  sORF finder: a program package to identify small open reading frames with high coding potential , 2010, Bioinform..

[54]  D. Elliott,et al.  Patterns, mechanisms, and functions of translation regulation in mammalian spermatogenic cells , 2004, Cytogenetic and Genome Research.

[55]  K. Gevaert,et al.  Deep Proteome Coverage Based on Ribosome Profiling Aids Mass Spectrometry-based Protein and Peptide Discovery and Provides Evidence of Alternative Translation Products and Near-cognate Translation Initiation Events* , 2013, Molecular & Cellular Proteomics.

[56]  M M Pooggin,et al.  Ribosome shunt is essential for infectivity of cauliflower mosaic virus. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[57]  Daniel N. Wilson,et al.  Structural basis for translational stalling by human cytomegalovirus and fungal arginine attenuator peptide. , 2010, Molecular cell.

[58]  L. Romão,et al.  Gene Expression Regulation by Upstream Open Reading Frames and Human Disease , 2013, PLoS genetics.

[59]  Klaus Wethmar,et al.  C/EBPbetaDeltauORF mice--a genetic model for uORF-mediated translational control in mammals. , 2010, Genes & development.

[60]  Armando Rodriguez.  What is MDM-2?: , 1994 .

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

[62]  Shuyun Dong,et al.  Genome-wide analysis of mRNAs regulated by the nonsense-mediated and 5' to 3' mRNA decay pathways in yeast. , 2003, Molecular cell.

[63]  Nicholas T. Ingolia,et al.  The translational landscape of mTOR signalling steers cancer initiation and metastasis , 2012, Nature.

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

[65]  A. Leutz,et al.  Translational control of C/EBP (cid:1) and C/EBP (cid:2) isoform expression , 2000 .

[66]  N. Elçioglu,et al.  Marie Unna hereditary hypotrichosis: A Turkish family with loss of eyebrows and a U2HR mutation , 2010, American journal of medical genetics. Part A.

[67]  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.

[68]  S. Rhee,et al.  Molecular cloning and characterization of the mouse peroxiredoxin V gene. , 2000, Biochemical and biophysical research communications.

[69]  N. Sonenberg,et al.  The requirement for eukaryotic initiation factor 4A (elF4A) in translation is in direct proportion to the degree of mRNA 5' secondary structure. , 2001, RNA.

[70]  Sumio Sugano,et al.  Analysis of small human proteins reveals the translation of upstream open reading frames of mRNAs. , 2004, Genome research.

[71]  S. Cichon,et al.  Marie Unna hereditary hypotrichosis: identification of a U2HR mutation in the family from the original 1925 report. , 2011, Journal of the American Academy of Dermatology.

[72]  A. Hinnebusch,et al.  Multiple upstream AUG codons mediate translational control of GCN4 , 1986, Cell.

[73]  M. Kozak,et al.  Effects of intercistronic length on the efficiency of reinitiation by eucaryotic ribosomes. , 1987, Molecular and cellular biology.

[74]  T. Hoang,et al.  Translational control of SCL-isoform expression in hematopoietic lineage choice. , 2003, Genes & development.

[75]  P. Johnson,et al.  Inhibition of CCAAT/Enhancer-binding Protein α and β Translation by Upstream Open Reading Frames* , 1998, The Journal of Biological Chemistry.

[76]  Julian N. Selley,et al.  Upstream sequence elements direct post-transcriptional regulation of gene expression under stress conditions in yeast , 2009, BMC Genomics.

[77]  M. Holcik,et al.  The translation of an antiapoptotic protein HIAP2 is regulated by an upstream open reading frame , 2003, Cell Death and Differentiation.

[78]  Sheng‐Chung Lee,et al.  Transgenic zebrafish model to study translational control mediated by upstream open reading frame of human chop gene , 2011, Nucleic acids research.

[79]  R. Skoda,et al.  An activating splice donor mutation in the thrombopoietin gene causes hereditary thrombocythaemia , 1998, Nature Genetics.

[80]  Markus Seiler,et al.  Translational Control via Protein-Regulated Upstream Open Reading Frames , 2011, Cell.

[81]  Michael Snyder,et al.  Extensive Transcript Diversity and Novel Upstream Open Reading Frame Regulation in Yeast , 2013, G3: Genes | Genomes | Genetics.

[82]  F. Messenguy,et al.  The leader peptide of yeast gene CPA1 is essential for the translational repression of its expression , 1987, Cell.

[83]  C Saccone,et al.  Analysis of oligonucleotide AUG start codon context in eukariotic mRNAs. , 2000, Gene.

[84]  Arun K. Ramani,et al.  High resolution transcriptome maps for wild-type and nonsense-mediated decay-defective Caenorhabditis elegans , 2009, Genome Biology.

[85]  K. Kleene.  Patterns, mechanisms, and functions of translation regulation in mammalian spermatogenic cells. , 2003, Cytogenetic and genome research.

[86]  D. Sabatini,et al.  A unifying model for mTORC1-mediated regulation of mRNA translation , 2012, Nature.

[87]  Sol Katzman,et al.  Frac-seq reveals isoform-specific recruitment to polyribosomes , 2013, Genome research.

[88]  Nicholas T. Ingolia,et al.  Ribosome Profiling of Mouse Embryonic Stem Cells Reveals the Complexity and Dynamics of Mammalian Proteomes , 2011, Cell.

[89]  Nicholas T. Ingolia,et al.  Genome-Wide Analysis in Vivo of Translation with Nucleotide Resolution Using Ribosome Profiling , 2009, Science.

[90]  J. F. Atkins,et al.  uORFs with unusual translational start codons autoregulate expression of eukaryotic ornithine decarboxylase homologs , 2008, Proceedings of the National Academy of Sciences.

[91]  M. Hentze,et al.  Position is the critical determinant for function of iron-responsive elements as translational regulators , 1992, Molecular and cellular biology.

[92]  Allan Jacobson,et al.  Ribosome occupancy of the yeast CPA1 upstream open reading frame termination codon modulates nonsense-mediated mRNA decay. , 2005, Molecular cell.

[93]  A. Zimmer,et al.  Regulation of RAR beta 2 mRNA expression: evidence for an inhibitory peptide encoded in the 5'-untranslated region , 1996, The Journal of cell biology.

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

[95]  David Hogg,et al.  Mutation of the CDKN2A 5' UTR creates an aberrant initiation codon and predisposes to melanoma , 1999, Nature Genetics.

[96]  R. Jackson,et al.  What determines whether mammalian ribosomes resume scanning after translation of a short upstream open reading frame? , 2004, Genes & development.

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

[98]  R. Werner,et al.  Variable promoter usage and alternative splicing in five mouse connexin genes. , 2005, Genomics.

[99]  O. A. Volkova,et al.  Hidden coding potential of eukaryotic genomes: nonAUG started ORFs , 2013, Journal of biomolecular structure & dynamics.

[100]  R. Betz,et al.  Identification of a U2HR gene mutation in Turkish families with Marie Unna hereditary hypotrichosis , 2009, Clinical and experimental dermatology.

[101]  J. McCarthy,et al.  Reinitiation and recycling are distinct processes occurring downstream of translation termination in yeast. , 2004, Journal of molecular biology.

[102]  Jae-Woo Cho,et al.  A novel mutation in Hr causes abnormal hair follicle morphogenesis in hairpoor mouse, an animal model for Marie Unna Hereditary Hypotrichosis , 2009, Mammalian Genome.

[103]  A. Leutz,et al.  Translational control of C/EBPalpha and C/EBPbeta isoform expression. , 2000, Genes & development.

[104]  F. Morlé,et al.  Negative and Translation Termination-Dependent Positive Control of FLI-1 Protein Synthesis by Conserved Overlapping 5′ Upstream Open Reading Frames in Fli-1 mRNA , 2000, Molecular and Cellular Biology.

[105]  L. Maquat,et al.  Quality control of eukaryotic mRNA: safeguarding cells from abnormal mRNA function. , 2007, Genes & development.

[106]  L. Ryabova,et al.  Short ORF-Dependent Ribosome Shunting Operates in an RNA Picorna-Like Virus and a DNA Pararetrovirus that Cause Rice Tungro Disease , 2012, PLoS pathogens.