Translational Regulation by Upstream Open Reading Frames and Its Relevance to Human Genetic Disease

Abstract

Upstream open reading frames (uORFs) are cis‐acting elements, located before or overlapped with the main coding ORF (mORF), that regulate cap‐dependent translation efficiency in a transcript‐specific manner. More than half of the human transcripts bear at least one uORF. In addition, it has been recently revealed that many of these uORFs initiate at non‐AUG codons, which significantly increases the complexity and diversity of the human translatome. These regulons are considered repressors of downstream translation but, in some biological contexts, they induce mORF expression. There are several the mechanisms by which AUG and non‐AUG uORFs regulate gene expression, allowing the cell to control transcript‐specific translation according to its needs. Also, we describe several examples of uORF genetic variants associated with human genetic diseases. Studying these cases and understanding the resultant abnormal mechanisms of uORF‐mediated translational control is of extreme importance for the development of new therapeutic strategies.

Key Concepts

  • Upstream open reading frames (uORFs) are cis‐acting translational regulatory elements present within the 5′ leader sequence of mRNAs.
  • uORFs can regulate gene expression by repressing or promoting translation of the downstream main ORF (mORF), according to the cellular environment.
  • The number of uORFs, the intercistronic distance, the overlap with the mORF and the context of the initiation codon are the uORF‐related structural features that most influence their translational regulatory capacity.
  • uORF‐mediated repression of mORF translation is usually achieved by ribosome dissociation, ribosome stalling, induction of nonsense‐mediated mRNA decay (NMD) or production of inhibitory peptides.
  • uORF‐mediated induction of mORF translation is usually achieved by ribosome bypass or translation reinitiation.
  • uORFs initiated by non‐AUG codons are more frequent than previously appreciated, having important biological functions.
  • uORF‐altering polymorphisms and mutations, which create, disrupt or change a uORF, can cause human genetic diseases.
  • Studying and understanding the uORF‐mediated mechanisms of gene expression regulation may provide knowledge to develop novel therapies for several human diseases.

Keywords: gene expression regulation; mRNA translation; translational control; upstream open reading frame (uORF); non‐AUG‐uORF; stress

Figure 1. Model of the canonical eukaryotic translation initiation process. The process begins with the assembly of the 43S PIC, with eIFs 1A, 1, 3 and 5 binding initially and stimulating recruitment of the TC, composed of eIF2, GTP and Met‐tRNAiMet. The 43S PIC attaches near the 5′ cap of the mRNA through interaction of eIF3 and eIF4G, which is part of the eIF4F complex (eIFs 4G, 4E and 4A), forming a 48S‐activated mRNA. The subsequent scanning of the mRNA from 5′ to 3′ is accompanied by GTP hydrolysis by the TC without releasing Pi. Base‐pairing between the start codon and the anti‐codon of the tRNAiMet at the P‐site promotes conformational changes within the PIC, with the consequent release of Pi, eIF1, and eIF2‐GDP in complex with eIF5. Then, eIF5B bound to GTP promotes joining of the 60S subunit, with release of eIF5B‐GDP and eIF1A to form the 80S ribosome, ready to continue with the elongation phase. The released eIF2‐GDP is then recycled to eIF2‐GTP by the exchange factor, eIF2B, to start a new round of translation initiation.
Figure 2. Ribosome stalling/dissociation at uORFs inhibits translation of CHOP and GADD34 mORFs. (a) During basal conditions, ribosomes initiate translation at CHOP uORF. Translation of an Ile‐Phe‐Ile sequence promotes ribosome stalling and prevents translation of CHOP mORF, causing low levels of CHOP expression. (b) During basal conditions, scanning ribosomes bypass the GADD34 uORF1 due to its poor start codon context and initiate translation at uORF2. Translation of a Pro‐Pro‐Gly peptide sequence juxtaposed to the uORF2 stop codon results in ribosome dissociation from the mRNA and causes low levels of GADD34 expression.
Figure 3. uORF‐mediated control of ATF4 expression in basal and stress conditions. (a) During normal conditions, ribosomes scanning the ATF4 mRNA initiate translation at uORF1. After termination, the 40S ribosomal subunits quickly reacquire a new ternary complex and reinitiate translation at uORF2, which overlaps out‐of‐frame with ATF4 mORF. Translation of uORF2 results in ribosome termination 3′ of the ATF4 initiation codon, which inhibits mORF translation. At the same time, the uORF2 stop codon is recognised as a premature termination codon (PTC), activating the NMD machinery that leads to mRNA decay. Altogether, these mechanisms contribute to low basal ATF4 expression at both protein and mRNA levels. (b) Elevated eIF2α‐P during stress conditions results in low ternary complex availability. Thus, after the translation of ATF4 uORF1, the post‐translation 40S ribosomal subunit scans through the inhibitory uORF2, reacquiring a new ternary complex in time to initiate translation at the ATF4 mORF. This mechanism of ‘delayed reinitiation’ allows the expression of ATF4 during cellular stress.
Figure 4. uORF‐mediated translation of GADD34 and CHOP mORFs during stress. (a) During stress conditions, elevated eIF2α‐P results in ribosomal bypass of GADD34 uORF1 and uORF2 due to their weak/moderate start codon contexts. Bypass of the inhibitory uORF2 results in increased translation initiation at the GADD34 mORF to promote GADD34 expression. (b) Increased eIF2α‐P during stress also promotes bypass of the inhibitory uORF of CHOP due to its weak start codon context, allowing translation initiation at the CHOP mORF to increase its expression.
Figure 5. Mechanistic and structural aspects that determine non‐AUG‐uORF recognition and their regulatory potential. (a) Different eIFs can contribute to non‐AUG start codon recognition during translation initiation. The eIF2 delivers the canonical Met (M)‐tRNAiMet for translation initiation at a non‐AUG codon in a GTP‐dependent manner, but with low efficiency (grey arrow). Alternatively, eIF2A and eIF2D can deliver the Met‐tRNAiMet or Leu (L)‐tRNA and Val (V)‐tRNA, respectively, to the non‐AUG codon, independently of GTP and with a higher efficiency (black arrows). (b) The abundance of specific eIFs can determine non‐AUG recognition during translation initiation. While increased levels of eIF2A, eIF2α‐P and eIF5 favour translation initiation at non‐AUG codons, high levels of eIF1 or eIF5‐mimic protein (5MP) increase the stringency of start codon selection. (c) The Kozak sequence context (in orange) of the non‐AUG codon can influence its recognition efficiency during translation initiation, as it does for AUG codons. (d) Formation of secondary structures, such as hairpins, downstream of a non‐AUG codon may momentarily pause or slow down the scanning 40S ribosome, providing time for recognition of the non‐optimal start codon and initiate translation.
close

References

Abastado JP, Miller PF, Jackson BM, et al. (1991) Suppression of ribosomal reinitiation at upstream open reading frames in amino acid‐starved cells forms the basis for GCN4 translational control. Molecular and cellular biology 11 (1): 486–496.

Akimoto C, Sakashita E, Kasashima K, et al. (2013) Translational repression of the McKusick‐Kaufman syndrome transcript by unique upstream open reading frames encoding mitochondrial proteins with alternative polyadenylation sites. Biochimica et biophysica acta 1830 (3): 2728–2738.

Algire MA, Maag D and Lorsch JR (2005) Pi release from eIF2, not GTP hydrolysis, is the step controlled by start‐site selection during eukaryotic translation initiation. Molecular Cell 20 (2): 251–262.

Aliouat A, Hatin I, Bertin P, et al. (2020) Divergent effects of translation termination factor eRF3A and nonsense‐mediated mRNA decay factor UPF1 on the expression of uORF carrying mRNAs and ribosome protein genes. RNA Biology 17 (2): 227–239.

Armata IA, Goode L, Davila E, et al. (2017) Translational effects and coding potential of an upstream open reading frame associated with DOPA Responsive Dystonia. Biochimica et Biophysica Acta‐Molecular Basis of Disease 1863 (6): 1171–1182.

Bach J, Endler G, Winkelmann BR, et al. (2008) Coagulation factor XII (FXII) activity, activated FXII, distribution of FXII C46T gene polymorphism and coronary risk. Journal of Thrombosis and Haemostasis 6 (2): 291–296.

Baird TD, Palam LR, Fusakio ME, et al. (2014) Selective mRNA translation during eIF2 phosphorylation induces expression of IBTKα. Molecular Biology of the Cell 25 (10): 1686–1697.

Barbosa C, Peixeiro I and Romão L (2013) Gene expression regulation by upstream open reading frames and human disease. PLoS Genetics 9 (8): e1003529.

Calvo SE, Pagliarini DJ and Mootha VK (2009) Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans. Proceedings of the National Academy of Sciences of the United States of America 106 (18): 7507–7512.

Chan W‐K, Bhalla AD, Le Hir H, et al. (2009) A UPF3‐mediated regulatory switch that maintains RNA surveillance. Nature Structural & Molecular Biology 16 (7): 747–753.

Cloutier P, Poitras C, Faubert D, et al. (2020) Upstream ORF‐encoded ASDURF is a novel prefoldin‐like subunit of the PAQosome. Journal of Proteome Research 19 (1): 18–27.

Col B, Oltean S and Banerjee R (2007) Translational regulation of human methionine synthase by upstream open reading frames. Biochimica et Biophysica Acta‐Gene Structure and Expression 1769 (9–10): 532–540.

Connor JH, Weiser DC, Li S, et al. (2001) Growth arrest and DNA damage‐inducible protein GADD34 assembles a novel signaling complex containing protein phosphatase 1 and inhibitor 1. Molecular and Cellular Biology 21 (20): 6841–6850.

Dmitriev SE, Terenin IM, Andreev DE, et al. (2010) GTP‐independent tRNA delivery to the ribosomal P‐site by a novel eukaryotic translation factor. Journal of Biological Chemistry 285 (35): 26779–26787.

Eliseev B, Yeramala L, Leitner A, et al. (2018) Structure of a human cap‐dependent 48S translation pre‐initiation complex. Nucleic Acids Research 46 (5): 2678–2689.

Fan Z, Zheng J, Xue Y, et al. (2018) NR2C2‐uORF targeting UCA1‐miR‐627‐5p‐NR2C2 feedback loop to regulate the malignant behaviors of glioma cells. Cell Death Discovery 9 (12): 1165.

Fernandes R, Nogueira G, da Costa PJ, et al. (2019) Nonsense‐mediated mRNA decay in development, stress and cancer. In: Romão L (ed.) Advances in Experimental Medicine and Biology, vol. 1157, pp 41–83. Springer: Cham.

Fringer JM, Acker MG, Fekete CA, et al. (2007) Coupled release of eukaryotic translation initiation factors 5B and 1A from 80S ribosomes following subunit joining. Molecular and cellular biology 27 (6): 2384–2397.

Gamble CE, Brule CE, Dean KM, et al. (2016) Adjacent codons act in concert to modulate translation efficiency in yeast. Cell 166 (3): 679–690.

Gao X, Wan J, Liu B, et al. (2015) Quantitative profiling of initiating ribosomes in vivo. Nature Methods 12 (2): 147–153.

Gardner LB (2008) Hypoxic inhibition of nonsense‐mediated RNA decay regulates gene expression and the integrated stress response. Molecular and cellular biology 28 (11): 3729–3741.

Goetz AE and Wilkinson M (2017) Stress and the nonsense‐mediated RNA decay pathway. Cellular and Molecular Life Sciences 74 (19): 3509–3531.

Grant CM and Hinnebusch AG (1994) Effect of sequence context at stop codons on efficiency of reinitiation in GCN4 translational control. Molecular and Cellular Biology 14 (1): 606–618.

Guenther UP, Weinberg DE, Zubradt MM, et al. (2018) The helicase Ded1p controls use of near‐cognate translation initiation codons in 5′ UTRs. Nature 559 (7712): 130–134.

Hann SR, King MW, Bentley DL, et al. (1988) A non‐AUG translational initiation in c‐myc exon 1 generates an N‐terminally distinct protein whose synthesis is disrupted in Burkitt's lymphomas. Cell 52 (2): 185–195.

Herrmannová A, Prilepskaja T, Wagner S, et al. (2020) Adapted formaldehyde gradient cross‐linking protocol implicates human eIF3d and eIF3c, k and l subunits in the 43S and 48S pre‐initiation complex assembly, respectively. Nucleic Acids Research 48 (4): 1969–1984.

Hershey JWB, Sonenberg N and Mathews MB (2012) Principles of translational control: an overview. Cold Spring Harbor Perspectives in Biology 4 (12): a011528.

Hinnebusch AG (2005) Translational regulation of GCN4 and the general amino acid control of yeast. Annual Review of Microbiology 59 (1): 407–450.

Hinnebusch AG (2006) eIF3: a versatile scaffold for translation initiation complexes. Trends in Biochemical Sciences 31 (10): 553–562.

Hinnebusch AG (2017) structural insights into the mechanism of scanning and start codon recognition in eukaryotic translation initiation. Trends in Biochemical Sciences 42 (8): 589–611.

Ho JJD, Balukoff NC, Cervantes G, et al. (2018) Oxygen‐sensitive remodeling of central carbon metabolism by archaic eIF5B. Cell Reports 22 (1): 17–26.

Hogg JR and Goff SP (2010) Upf1 senses 3′UTR length to potentiate mRNA decay. Cell 143 (3): 379–389.

Hronová V, Mohammad MP, Wagner S, et al. (2017) Does eIF3 promote reinitiation after translation of short upstream ORFs also in mammalian cells? RNA Biology 14 (12): 1660–1667.

Hussain T, Llácer JL, Fernández IS, et al. (2014) Structural changes enable start codon recognition by the eukaryotic translation initiation complex. Cell 159 (3): 597–607.

Hwang WL and Su TS (1998) Translational regulation of hepatitis B virus polymerase gene by termination‐reinitiation of an upstream minicistron in a length‐dependent manner. Journal of General Virology 79 (9): 2181–2189.

Ingolia NT, Ghaemmaghami S, Newman JRS, et al. (2009) Genome‐wide analysis in vivo of translation with nucleotide resolution using ribosome profiling. Science 324 (5924): 218–223.

Ingolia NT (2010) Genome‐wide translational profiling by ribosome footprinting. Methods in Enzymology 470: 119–142.

Ingolia NT, Lareau LF and Weissman JS (2011) Ribosome profiling of mouse embryonic stem cells reveals the complexity and dynamics of mammalian proteomes. Cell 147 (4): 789–802.

Ivanov IP, Loughran G, Sachs MS, et al. (2010) Initiation context modulates autoregulation of eukaryotic translation initiation factor 1 (eIF1). Proceedings of the National Academy of Sciences of the United States of America 107 (42): 18056–18060.

Ivanov A, Mikhailova T, Eliseev B, et al. (2016) PABP enhances release factor recruitment and stop codon recognition during translation termination. Nucleic acids research 44 (16): 7766–7776.

Ivanov IP, Shin BS, Loughran G, et al. (2018) Polyamine control of translation elongation regulates start site selection on antizyme inhibitor mRNA via Ribosome queuing. Molecular Cell 70 (2): 254–264.e6.

Jennings MD, Zhou Y, Mohammad‐Qureshi SS, et al. (2013) eIF2B promotes eIF5 dissociation from eIF2*GDP to facilitate guanine nucleotide exchange for translation initiation. Genes & Development 27 (24): 2696–2707.

Jennings MD, Kershaw CJ, Adomavicius T, et al. (2017) Fail‐safe control of translation initiation by dissociation of eIF2α phosphorylated ternary complexes. eLife 6: e24542.

Johnstone TG, Bazzini AA and Giraldez AJ (2016) Upstream ORFs are prevalent translational repressors in vertebrates. The EMBO Journal 35 (7): 706–723.

Jousse C, Bruhat A, Carraro V, et al. (2001) Inhibition of CHOP translation by a peptide encoded by an open reading frame localized in the chop 5′UTR. Nucleic acids research 29 (21): 4341–4351.

Kearse MG and Wilusz JE (2017) Non‐AUG translation: a new start for protein synthesis in eukaryotes. Genes & development 31 (17): 1717–1731.

Khan YA, Jungreis I, Wright JC, et al. (2020) Evidence for a novel overlapping coding sequence in POLG initiated at a CUG start codon. BMC Genetics 21: 25.

Kitano S, Kurasawa H and Aizawa Y (2018) Transposable elements shape the human proteome landscape via formation of cis‐acting upstream open reading frames. Genes to Cells 23 (4): 274–284.

Kozak M (1986) Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes. Cell 44 (2): 283–292.

Kozak M (1987a) At least six nucleotides preceding the AUG initiator codon enhance translation in mammalian cells. Journal of Molecular Biology 196 (4): 947–950.

Kozak M (1987b) Effects of intercistronic length on the efficiency of reinitiation by eucaryotic ribosomes. Molecular and Cellular Biology 7 (10): 3438–3445.

Kozak M (1989) Context effects and inefficient initiation at non‐AUG codons in eucaryotic cell‐free translation systems. Molecular and Cellular Biology 9 (11): 5073–5080.

Kozak M (1990) Downstream secondary structure facilitates recognition of initiator codons by eukaryotic ribosomes. Proceedings of the National Academy of Sciences of the United States of America 87 (21): 8301–8305.

Kozak M (2001) Constraints on reinitiation of translation in mammals. Nucleic acids research 29 (24): 5226–5232.

Law GL, Raney A, Heusner C, et al. (2001) Polyamine regulation of ribosome pausing at the upstream open reading frame of S‐adenosylmethionine decarboxylase. Journal of Biological Chemistry 276 (41): 38036–38043.

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

Lee Y‐Y, Cevallos RC and Jan E (2009) An upstream open reading frame regulates translation of GADD34 during cellular stresses that induce eIF2alpha phosphorylation. The Journal of biological chemistry 284 (11): 6661–6673.

Lin KY, Nag N, Pestova TV, et al. (2018) Human eIF5 and eIF1A compete for binding to eIF5B. Biochemistry 57 (40): 5910–5920.

Lin Y, May GE, Kready H, et al. (2019) Impacts of uORF codon identity and position on translation regulation. Nucleic Acids Research 47 (17): 9358–9367.

Liu L, Dilworth D, Gao L, et al. (1999) Mutation of the CDKN2A 5′ UTR creates an aberrant initiation codon and predisposes to melanoma. Nature Genetics 21 (1): 128–132.

Loughran G, Sachs MS, Atkins JF, et al. (2012) Stringency of start codon selection modulates autoregulation of translation initiation factor eIF5. Nucleic Acids Research 40 (7): 2898–2906.

Lu PD, Harding HP and Ron D (2004) Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response. Journal of Cell Biology 167 (1): 27–33.

Luukkonen BG, Tan W and Schwartz S (1995) 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. Journal of virology 69 (7): 4086–4094.

Maag D, Fekete CA, Gryczynski Z, et al. (2005) A conformational change in the eukaryotic translation preinitiation complex and release of eIF1 signal recognition of the start codon. Molecular Cell 17 (2): 265–275.

Maquat LE, Kinniburgh AJ, Rachmilewitz EA, et al. (1981) Unstable β‐globin mRNA in mRNA‐deficient β0 thalassemia. Cell 27 (3): 543–553.

Maquat LE (2004) Nonsense‐mediated mRNA decay: splicing, translation and mRNP dynamics. Nature Reviews Molecular Cell Biology 5 (2): 89–99.

Marciniak SJ, Yun CY, Oyadomari S, et al. (2004) CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes and Development 18 (24): 3066–3077.

Matsui M, Yachie N, Okada Y, et al. (2007) Bioinformatic analysis of post‐transcriptional regulation by uORF in human and mouse. FEBS Letters 581 (22): 4184–4188.

Mendell JT, Sharifi NA, Meyers JL, et al. (2004) Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise. Nature genetics 36 (10): 1073–1078.

Miller PF and Hinnebusch AG (1989) Sequences that surround the stop codons of upstream open reading frames in GCN4 mRNA determine their distinct functions in translational control. Genes & development 3 (8): 1217–1225.

Mohammad MP, Munzarová Pondelícková V, Zeman J, et al. (2017) In vivo evidence that eIF3 stays bound to ribosomes elongating and terminating on short upstream ORFs to promote reinitiation. Nucleic acids research 45 (5): 2658–2674.

Munzarová V, Pánek J, Gunišová S, et al. (2011) Translation reinitiation relies on the interaction between eIFa/TIF32 and progressively folded cis‐acting mRNA elements preceding short uORFS. PLoS Genetics 7 (7): e1002137.

Neu‐Yilik G, Raimondeau E, Eliseev B, et al. (2017) Dual function of UPF3B in early and late translation termination. The EMBO Journal 36 (20): 2968–2986.

Novoa I, Zeng H, Harding HP, et al. (2001) Feedback inhibition of the unfolded protein response by GADD34‐mediated dephosphorylation of eIF2α. Journal of Cell Biology 153 (5): 1011–1021.

Occhi G, Regazzo D, Trivellin G, et al. (2013) A novel mutation in the upstream open reading frame of the CDKN1B gene causes a MEN4 phenotype. PLoS Genetics 9 (3): e1003350.

Pakos‐Zebrucka K, Koryga I, Mnich K, et al. (2016) The integrated stress response. EMBO reports 17 (10): 1374–1395.

Palam LR, Baird TD and Wek RC (2011) Phosphorylation of eIF2 facilitates ribosomal bypass of an inhibitory upstream ORF to enhance CHOP translation. The Journal of biological chemistry 286 (13): 10939–10949.

Passmore LA, Schmeing TM, Maag D, et al. (2007) The eukaryotic translation initiation factors eIF1 and eIF1A induce an open conformation of the 40S ribosome. Molecular cell 26 (1): 41–50.

Peabody DS (1989) Translation initiation at non‐AUG triplets in mammalian cells. Journal of Biological Chemistry 264 (9): 5031–5035.

Pendleton LC, Goodwin BL, Flam BR, et al. (2002) Endothelial argininosuccinate synthase mRNA 5′‐untranslated region diversity: infrastructure for tissue‐specific expression. Journal of Biological Chemistry 277 (28): 25363–25369.

Pendleton LC, Goodwin BL, Solomonson LP, et al. (2005) Regulation of endothelial argininosuccinate synthase expression and NO production by an upstream open reading frame. Journal of Biological Chemistry 280 (25): 24252–24260.

Pestova TV and Kolupaeva VG (2002) The roles of individual eukaryotic translation initiation factors in ribosomal scanning and initiation codon selection. Genes and Development 16 (22): 2906–2922.

Pestova TV, Lomakin IB, Lee JH, et al. (2000) The joining of ribosomal subunits in eukaryotes requires eIF5B. Nature 403 (6767): 332–335.

Pisarev AV, Kolupaeva VG and Pisareva VP (2006) Specific functional interactions of nucleotides at key ‐3 and +4 positions flanking the initiation codon with components of the mammalian 48S translation initiation complex. Genes and Development 20 (5): 624–636.

Pöyry TAA, Kaminski A and Jackson RJ (2004) What determines whether mammalian ribosomes resume scanning after translation of a short upstream open reading frame? Genes and Development 18 (1): 62–75.

Presnyak V, Alhusaini N, Chen YH, et al. (2015) Codon optimality is a major determinant of mRNA stability. Cell 160 (6): 1111–1124.

Raney A, Lynn Law G, Mize GJ, et al. (2002) Regulated translation termination at the upstream open reading frame in S‐adenosylmethionine decarboxylase mRNA. Journal of Biological Chemistry 277 (8): 5988–5994.

Rodriguez CM, Chun SY, Mills RE, et al. (2019) Translation of upstream open reading frames in a model of neuronal differentiation. BMC Genomics 20: 391.

Rogers GW, Richter NJ, Lima WF, et al. (2001) Modulation of the helicase activity of eIF4A by eIF4B, eIF4H, and eIF4F. Journal of Biological Chemistry 276 (33): 30914–30922.

Romanelli Tavares VL, Kague E, Musso CM, et al. (2019) Craniofrontonasal syndrome caused by introduction of a novel uATG in the 5′UTR of EFNB1. Molecular Syndromology 10 (1–2): 40–47.

Scholz A, Rappl P, Böffinger N, et al. (2019) Translation of TNFAIP2 is tightly controlled by upstream open reading frames. Cellular and Molecular Life Sciences.

Sendoel A, Dunn JG, Rodriguez EH, et al. (2017) Translation from unconventional 5′ start sites drives tumour initiation. Nature 541 (7638): 494–499.

Shi Y, Wu J, Zhong T, et al. (2020) Upstream ORFs prevent MAVS spontaneous aggregation and regulate innate immune homeostasis. iScience 23 (5): 101059.

Silva J, Fernandes R and Romão L (2017) Gene expression regulation by upstream open reading frames in rare diseases. Journal of Rare Diseases Research and Treatment. 2 (4): 33–38.

Silva J, Fernandes R and Romão L (2019) Translational regulation by upstream open reading frames and human diseases. In: Romão L (ed.) Advances in Experimental Medicine and Biology, vol. 1157, pp 99–116. Springer: Cham.

Singh G, Rebbapragada I and Lykke‐Andersen J (2008) A competition between stimulators and antagonists of Upf complex recruitment governs human nonsense‐mediated mRNA decay. PLoS biology 6 (4): e111.

Siridechadilok B, Fraser CS, Hall RJ, et al. (2005) Structural roles for human translation factor elF3 in initiation of protein synthesis. Science 310 (5753): 1513–1515.

Skabkin MA, Skabkina OV, Dhote V, et al. (2010) Activities of Ligatin and MCT‐1/DENR in eukaryotic translation initiation and ribosomal recycling. Genes & development 24 (16): 1787–1801.

Slavoff SA, Mitchell AJ, Schwaid AG, et al. (2013) Peptidomic discovery of short open reading frame‐encoded peptides in human cells. Nature Chemical Biology 9 (1): 59–64.

Spealman P, Naik AW, May GE, et al. (2018) Conserved non‐AUG uORFs revealed by a novel regression analysis of ribosome profiling data. Genome Research 28 (2): 214–222.

Starck SR, Jiang V, Pavon‐Eternod M, et al. (2012) Leucine‐tRNA initiates at cug start codons for protein synthesis and presentation by MHC class I. Science 336 (6089): 1719–1723.

Starck SR, Tsai JC, Chen K, et al. (2016) Translation from the 5′ untranslated region shapes the integrated stress response. Science 351 (6272): aad3867.

Stockklausner C, Breit S, Neu‐Yilik G, et al. (2006) The uORF‐containing thrombopoietin mRNA escapes nonsense‐mediated decay (NMD). Nucleic acids research 34 (8): 2355–2363.

Szamecz B, Rutkai E, Cuchalová L, et al. (2008) eIF3a cooperates with sequences 5′ of uORF1 to promote resumption of scanning by post‐termination ribosomes for reinitiation on GCN4 mRNA. Genes and Development 22 (17): 2414–2425.

Tang L, Morris J, Wan J, et al. (2017) Competition between translation initiation factor eIF5 and its mimic protein 5MP determines non‐AUG initiation rate genome‐wide. Nucleic acids research 45 (20): 11941–11953.

Tani H, Imamachi N, Salam KA, et al. (2012) Identification of hundreds of novel UPF1 target transcripts by direct determination of whole transcriptome stability. RNA biology 9 (11): 1370–1379.

Teske BF, Fusakio ME, Zhou D, et al. (2013) CHOP induces activating transcription factor 5 (ATF5) to trigger apoptosis in response to perturbations in protein homeostasis. Molecular Biology of the Cell 24 (15): 2477–2490.

Tirado I, Soria JM, Mateo J, et al. (2004) Association after linkage analysis indicates that homozygosity for the 46C→T polymorphism in the Fl2 gene is a genetic risk factor for venous thrombosis. Thrombosis and Haemostasis 91 (5): 899–904.

Torrance V and Lydall D (2018) Overlapping open reading frames strongly reduce human and yeast STN1 gene expression and affect telomere function. PLOS Genetics 14 (8): e1007523.

Twigg SRF, Babbs C, van den Elzen MEP, et al. (2013) Cellular interference in craniofrontonasal syndrome: males mosaic for mutations in the X‐linked EFNB1 gene are more severely affected than true hemizygotes. Human molecular genetics 22 (8): 1654–1662.

Vattem KM and Wek RC (2004) Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Proceedings of the National Academy of Sciences of the United States of America 101 (31): 11269–11274.

Wang M, Yang C, Liu X, et al. (2020a) An upstream open reading frame regulates vasculogenic mimicry of glioma via ZNRD1‐AS1/miR‐499a‐5p/ELF1/EMI1 pathway. Journal of Cellular and Molecular Medicine (Online ahead of print).

Wang Y, Yang C, Liu X, et al. (2020b) Transcription factor AP‐4 (TFAP4)‐upstream ORF coding 66 aa inhibits the malignant behaviors of glioma cells by suppressing the TFAP4/long noncoding RNA 00520/microRNA‐520f‐3p feedback loop. Cancer Science 111 (3): 891–906.

Wen Y, Liu Y, Xu Y, et al. (2009) Loss‐of‐function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis. Nature Genetics 41 (2): 228–233.

Wethmar K, Schulz J, Muro EM, et al. (2016) Comprehensive translational control of tyrosine kinase expression by upstream open reading frames. Oncogene 35 (13): 1736–1742.

Xiong M, Wang Y‐Y, Guo W‐W, et al. (2020) A common variant rs2272804 in the 5′UTR of RIBC2 inhibits downstream gene expression by creating an upstream open reading frame. European Review for Medical and Pharmacological Sciences 24 (7): 3839–3848.

Ye Y, Liang Y, Yu Q, et al. (2015) Analysis of human upstream open reading frames and impact on gene expression. Human Genetics 134 (6): 605–612.

Yepiskoposyan H, Aeschimann F, Nilsson D, et al. (2011) Autoregulation of the nonsense‐mediated mRNA decay pathway in human cells. RNA 17 (12): 2108–2118.

Young SK, Willy JA, Wu C, et al. (2015) Ribosome reinitiation directs gene‐specific translation and regulates the integrated stress response. Journal of Biological Chemistry 290 (47): 28257–28271.

Young SK and Wek RC (2016) Upstream open reading frames differentially regulate gene‐specific translation in the integrated stress response. Journal of Biological Chemistry 291 (33): 16927–16935.

Young SK, Baird TD and Wek RC (2016a) Translation regulation of the glutamyl‐prolyl‐tRNA synthetase gene EPRS through bypass of upstream open reading frames with noncanonical initiation codons. Journal of Biological Chemistry 291 (20): 10824–10835.

Young SK, Palam LR, Wu C, et al. (2016b) Elongation stall directs gene‐specific translation in the integrated stress response. Journal of Biological Chemistry 291 (12): 6546–6558.

Yu CH, Dang Y, Zhou Z, et al. (2015) Codon usage influences the local rate of translation elongation to regulate Co‐translational protein folding. Molecular Cell 59 (5): 744–754.

Zach L, Braunstein I and Stanhill A (2014) Stress‐induced start codon fidelity regulates arseniteinducible regulatory particle‐associated protein (AIRAP) translation. Journal of Biological Chemistry 289 (30): 20706–20716.

Zhang W, Kassels AC, Barrington A, et al. (2019) Macular corneal dystrophy with isolated peripheral Descemet membrane deposits. American Journal of Ophthalmology Case Reports 16: 100571.

Zhou Y, Koelling N, Fenwick AL, et al. (2018) Disruption of TWIST1 translation by 5′ UTR variants in Saethre‐Chotzen syndrome. Human Mutation 39 (10): 1360–1365.

Zhou F, Zhang H, Kulkarni SD, et al. (2020) eIF1 discriminates against suboptimal initiation sites to prevent excessive uORF translation genome‐wide. RNA 26 (4): 419–438.

Zitomer RS, Walthall DA, Rymond BC, et al. (1984) Saccharomyces cerevisiae ribosomes recognize non‐AUG initiation codons. Molecular and Cellular Biology 4 (7): 1191–1197.

Further Reading

Gebauer F and Hentze M (2004) Molecular mechanisms of translational control. Nature Reviews Molecular Cell Biology 5 (10): 827–835.

Jackson R, Hellen C and Pestova T (2010) The mechanism of eukaryotic translation initiation and principles of its regulation. Nature Reviews Molecular Cell Biology 11 (2): 113–127.

Leppek K, Das R and Barna M (2018) Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them. Nature Reviews Molecular Cell Biology 19 (3): 158–174.

Sonenberg N and Hinnebusch A (2009) Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 136 (4): 731–745.

Wethmar K (2014) The regulatory potential of upstream open reading frames in eukaryotic gene expression. Wiley interdisciplinary reviews RNA 5 (6): 765–778.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Fernandes, Rafael, and Romão, Luísa(Sep 2020) Translational Regulation by Upstream Open Reading Frames and Its Relevance to Human Genetic Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0029194]