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Translation regulation by 5′ transcript leader cis-elements

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5' TL elements regulate translation initiation.

Translation regulation by 5′ transcript leader cis-elements is a process in cellular translation.

Background

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Gene expression is tightly controlled at many different stages. Alterations in translation of mRNA into proteins rapidly modulates the proteome without changing upstream steps such as transcription, pre-mRNA splicing, and nuclear export.[1] The strict regulation of translation in both space and time is in part governed by cis-regulatory elements located in 5′ mRNA transcript leaders (TLs) and 3′ untranslated regions (UTRs).

Due to their role in translation initiation, mRNA 5′ transcript leaders (TLs) strongly influence protein expression.[2][3][4] Eukaryotic translation consists of three stages: initiation elongation, and termination. Translation is primary regulated at the initiation stage where the small ribosomal subunit and initiation factors are recruited to the mRNA; directionally scanning along the 5′ TL to select the first “best” start codon to begin protein synthesis.[5] Cap-dependent ribosomal scanning accounts for 95-97% of all translation in eukaryotes under normal conditions.[6] Therefore, the cis-regulatory elements in TLs greatly influence translation initiation and ultimately protein expression.

Kozak consensus sequence

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The first step in initiation is formation of the pre-initiation complex, 48S PIC. The small ribosomal subunit and various eukaryotic initiation factors are recruited to the mRNA 5′ TL and to form the 48S PIC complex, which scans 5′ to 3′ along the mRNA transcript, inspecting each successive triplet for a functional start codon.[7][8] Translation initiation is most successful at an AUG codon surrounded upstream and downstream by a favorable sequence known as the “Kozak consensus sequence” or “Kozak context”.[9] (See A) Weak or absent Kozak context surrounding the AUG leads to “leaky” scanning where the start codon is skipped, whereas a strong Kozak context leads to start codon recognition by the 48S PIC and binding of Met-tRNAi in the “closed” state. Recent studies suggest that initiation occurs surprisingly often in eukaryotes at Near Cognate Codons (NCCs), which differ from AUG by one nucleotide.[10][11] Eukaryotic initiation factors rearrange the 48S PIC and permit the large subunit to join, thus forming the complete translation competent 80S ribosome.[12]

uORFs

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Upstream open reading frames (uORFs) in the 5′ TLs typically inhibit translation of the downstream main protein coding region (CDS).[13][14] (See B) Translation suppression of the CDS is attributable to the 5′ to 3′ directional nature of 48S PIC scanning. After successfully translating the uORF, the ribosome dissociates from the mRNA as part of termination before it can reach and translate the CDS. This destabilization of the translational machinery can trigger nonsense mediated decay of the mRNA transcript. However, in some cases uORFs will actually enhance the translation of the downstream CDS. For example, in S. cerevisiae, the gene GCN4 has a 5′ TL with multiple uORFs. The uORFs closest to the 5′ cap protect the CDS from the inhibitory activities of the downstream uORFs located closer to the CDS.[15] In summary, uORFs generally decease translation of the main ORF, but they are also capable of increasing protein synthesis under certain circumstances.

Secondary structure

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The 3-dimensional structure of the 5′ TL may also impact translation. (See C) Stem-loops have been demonstrated to both inhibit and enhance translation. Stem-loops can prevent cap binding and efficient 48S PIC scanning. Conversely, downstream stem-loops may increase the probability of translation initiation at start codons with a weak Kozak context, possibly by blocking scanning.[16][17][18] Besides stem-loops, other higher order structures such as G-quadraplexes and pseudoknots also impede eukaryotic translation.[19] To overcome translati on suppression by structures, DEAD-box RNA helicases unwind RNA structures, promoting scanning through the 5′ TL.[20]

Alternative transcript leaders

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Multiple transcription start sites may be used for the same gene generating alternative 5′ TLs with varied length and regulatory features. (See D)This is especially common in organisms with relatively compact genomes such as yeasts. In S. cerevisiae, alternative transcription start sites generate long alternative mRNA TLs with substantially lower translation efficiencies.[21] Counterintuitively, upstream transcriptional induction of these genes actually silences their expression during meiosis by blocking translation.[22][23] Furthermore, alternative transcription initiation within the CDS may generate protein isoforms with varied functions in S. cerevisiae.[24] These examples from the model organism S. cerevisiae suggest that mRNA transcripts with alternative 5′ TLs may have a regulatory function in eukaryotes especially during events requiring proteome remodeling such as meiosis and stress responses.

References

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  1. ^ Akirtava, Christina; McManus, Charles Joel (2021). "Control of translation by eukaryotic mRNA transcript leaders—Insights from high-throughput assays and computational modeling". WIREs RNA. 12 (3): e1623. doi:10.1002/wrna.1623. PMC 7914273. PMID 32869519.
  2. ^ Li, Jingyi Jessica; Chew, Guo-Liang; Biggin, Mark Douglas (2019-08-09). "Quantitative principles of cis-translational control by general mRNA sequence features in eukaryotes". Genome Biology. 20 (1): 162. doi:10.1186/s13059-019-1761-9. PMC 6689182. PMID 31399036.
  3. ^ Li, Jingyi Jessica; Chew, Guo-Liang; Biggin, Mark D. (2017-11-16). "Quantitating translational control: mRNA abundance-dependent and independent contributions and the mRNA sequences that specify them". Nucleic Acids Research. 45 (20): 11821–11836. doi:10.1093/nar/gkx898. PMC 5714229. PMID 29040683.
  4. ^ Weinberg, David E.; Shah, Premal; Eichhorn, Stephen W.; Hussmann, Jeffrey A.; Plotkin, Joshua B.; Bartel, David P. (2016-02-23). "Improved Ribosome-Footprint and mRNA Measurements Provide Insights into Dynamics and Regulation of Yeast Translation". Cell Reports. 14 (7): 1787–1799. doi:10.1016/j.celrep.2016.01.043. PMC 4767672. PMID 26876183.
  5. ^ Hinnebusch, Alan G. (September 2011). "Molecular Mechanism of Scanning and Start Codon Selection in Eukaryotes". Microbiology and Molecular Biology Reviews. 75 (3): 434–467. doi:10.1128/MMBR.00008-11. PMC 3165540. PMID 21885680.
  6. ^ Merrick, William C. (2004-05-12). "Cap-dependent and cap-independent translation in eukaryotic systems". Gene. 332: 1–11. doi:10.1016/j.gene.2004.02.051. PMID 15145049.
  7. ^ Sonenberg, Nahum; Dever, Thomas E. (February 2003). "Eukaryotic translation initiation factors and regulators". Current Opinion in Structural Biology. 13 (1): 56–63. doi:10.1016/s0959-440x(03)00009-5. PMID 12581660.
  8. ^ Richter, Joel D.; Sonenberg, Nahum (February 2005). "Regulation of cap-dependent translation by eIF4E inhibitory proteins". Nature. 433 (7025): 477–480. Bibcode:2005Natur.433..477R. doi:10.1038/nature03205. PMID 15690031. S2CID 4347657.
  9. ^ Kozak, M (1987-10-26). "An analysis of 5'-noncoding sequences from 699 vertebrate messenger RNAs". Nucleic Acids Research. 15 (20): 8125–8148. doi:10.1093/nar/15.20.8125. PMC 306349. PMID 3313277.
  10. ^ Eisenberg, Amy R.; Higdon, Andrea L.; Hollerer, Ina; Fields, Alexander P.; Jungreis, Irwin; Diamond, Paige D.; Kellis, Manolis; Jovanovic, Marko; Brar, Gloria A. (2020-08-26). "Translation Initiation Site Profiling Reveals Widespread Synthesis of Non-AUG-Initiated Protein Isoforms in Yeast". Cell Systems. 11 (2): 145–160.e5. doi:10.1016/j.cels.2020.06.011. PMC 7508262. PMID 32710835.
  11. ^ Ingolia, Nicholas T. (March 2014). "Ribosome profiling: new views of translation, from single codons to genome scale". Nature Reviews Genetics. 15 (3): 205–213. doi:10.1038/nrg3645. PMID 24468696. S2CID 13069682.
  12. ^ Hinnebusch, Alan G. (August 2017). "Structural Insights into the Mechanism of Scanning and Start Codon Recognition in Eukaryotic Translation Initiation". Trends in Biochemical Sciences. 42 (8): 589–611. doi:10.1016/j.tibs.2017.03.004. PMID 28442192.
  13. ^ Wethmar, Klaus (November 2014). "The regulatory potential of upstream open reading frames in eukaryotic gene expression". Wiley Interdisciplinary Reviews. RNA. 5 (6): 765–778. doi:10.1002/wrna.1245. PMID 24995549. S2CID 37819848.
  14. ^ Young, Sara K.; Wek, Ronald C. (2016-08-12). "Upstream Open Reading Frames Differentially Regulate Gene-specific Translation in the Integrated Stress Response". The Journal of Biological Chemistry. 291 (33): 16927–16935. doi:10.1074/jbc.R116.733899. PMC 5016099. PMID 27358398.
  15. ^ Hinnebusch, Alan G. (October 2005). "Translational Regulation Ofgcn4And the General Amino Acid Control of Yeast". Annual Review of Microbiology. 59 (1): 407–450. doi:10.1146/annurev.micro.59.031805.133833. PMID 16153175.
  16. ^ Cigan, A M; Pabich, E K; Donahue, T F (July 1988). "Mutational analysis of the HIS4 translational initiator region in Saccharomyces cerevisiae". Molecular and Cellular Biology. 8 (7): 2964–2975. doi:10.1128/mcb.8.7.2964. PMC 363516. PMID 3043201.
  17. ^ Kozak, M (November 1989). "Circumstances and mechanisms of inhibition of translation by secondary structure in eucaryotic mRNAs". Molecular and Cellular Biology. 9 (11): 5134–5142. doi:10.1128/mcb.9.11.5134. PMC 363665. PMID 2601712.
  18. ^ Kozak, M. (November 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. Bibcode:1990PNAS...87.8301K. doi:10.1073/pnas.87.21.8301. PMC 54943. PMID 2236042.
  19. ^ Leppek, Kathrin; Das, Rhiju; Barna, Maria (March 2018). "Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them". Nature Reviews Molecular Cell Biology. 19 (3): 158–174. doi:10.1038/nrm.2017.103. PMC 5820134. PMID 29165424.
  20. ^ Hilliker, Angela; Gao, Zhaofeng; Jankowsky, Eckhard; Parker, Roy (2011-09-16). "The DEAD-box protein Ded1 modulates translation by the formation and resolution of an eIF4F-mRNA complex". Molecular Cell. 43 (6): 962–972. doi:10.1016/j.molcel.2011.08.008. PMC 3268518. PMID 21925384.
  21. ^ Cheng, Ze; Otto, George Maxwell; Powers, Emily Nicole; Keskin, Abdurrahman; Mertins, Philipp; Carr, Steven Alfred; Jovanovic, Marko; Brar, Gloria Ann (2018-02-22). "Pervasive, Coordinated Protein-Level Changes Driven by Transcript Isoform Switching during Meiosis". Cell. 172 (5): 910–923.e16. doi:10.1016/j.cell.2018.01.035. PMC 5826577. PMID 29474919.
  22. ^ Rojas-Duran, Maria F.; Gilbert, Wendy V. (December 2012). "Alternative transcription start site selection leads to large differences in translation activity in yeast". RNA. 18 (12): 2299–2305. doi:10.1261/rna.035865.112. PMC 3504680. PMID 23105001.
  23. ^ Arribere, Joshua A.; Gilbert, Wendy V. (June 2013). "Roles for transcript leaders in translation and mRNA decay revealed by transcript leader sequencing". Genome Research. 23 (6): 977–987. doi:10.1101/gr.150342.112. PMC 3668365. PMID 23580730.
  24. ^ Wei, Wu; Hennig, Bianca P.; Wang, Jingwen; Zhang, Yujie; Piazza, Ilaria; Sanchez, Yerma Pareja; Chabbert, Christophe D.; Adjalley, Sophie H.; Steinmetz, Lars M.; Pelechano, Vicent (2019-11-18). "Chromatin-sensitive cryptic promoters putatively drive expression of alternative protein isoforms in yeast". Genome Research. 29 (12): 1974–1984. doi:10.1101/gr.243378.118. PMC 6886497. PMID 31740578.
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