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Related Concept Videos

Leaky Scanning02:28

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During most eukaryotic translation processes, the small 40S ribosome subunit scans an mRNA from its 5' end until it encounters the first start AUG codon. The large 60S ribosomal subunit then joins the smaller one to initiate protein synthesis. The location of the translation initiation is largely determined by the nucleotides near the start codon as there may be multiple translation initiation sites present on the mRNA.  Marilyn Kozak discovered that the sequence RCCAUGG (where R...
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Translational regulation in prokaryotes ensures efficient protein synthesis by controlling ribosome access to mRNA. This regulation is mediated by secondary RNA structures, including translational riboswitches, RNA thermometers, and small RNAs (sRNAs), which respond to intracellular and environmental signals to modulate gene expression.Translational RiboswitchesRiboswitches in the leader region of mRNAs can regulate translation by altering the accessibility of the Shine-Dalgarno (SD) sequence,...
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Improving Translational Accuracy02:07

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Base complementarity between the three base pairs of mRNA codon and the tRNA anticodon is not a failsafe mechanism. Inaccuracies can range from a single mismatch to no correct base pairing at all. The free energy difference between the correct and nearly correct base pairs can be as small as 3 kcal/ mol. With complementarity being the only proofreading step, the estimated error frequency would be one wrong amino acid in every 100 amino acids incorporated. However, error frequencies observed in...
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Initiation of Translation02:33

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Initiating translation is complex because it involves multiple molecules. Initiator tRNA, ribosomal subunits, and eukaryotic initiation factors (eIFs) are all required to assemble on the initiation codon of mRNA. This process consists of several steps that are mediated by different eIFs.
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Regulation of Expression at Multiple Steps01:23

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The gene expression in cells is regulated at different stages: (i) transcription, (ii) RNA processing, (iii) RNA localization, and (iv) translation. Transcriptional regulation is mediated by regulatory proteins such as transcription factors, activators, or repressors—these control gene expression by initiating or inhibiting the transcription of genes. Once a precursor or pre-mRNA is produced, it undergoes post-transcriptional modification, including 5' capping, splicing, and the...
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Transcriptional Regulation: Riboswitches01:23

Transcriptional Regulation: Riboswitches

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Riboswitches are RNA elements that regulate gene expression by altering their secondary structures in response to specific effector molecules. These elements, located in the leader regions of certain mRNAs, act as transcriptional regulators by toggling between alternative conformations to control downstream gene expression. Riboswitch-mediated regulation is a precise mechanism for modulating biosynthetic pathways, as exemplified by the riboflavin biosynthesis pathway in Bacillus...
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Toeprinting Analysis of Translation Initiation Complex Formation on Mammalian mRNAs
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Toeprinting Analysis of Translation Initiation Complex Formation on Mammalian mRNAs

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Translational regulation by uORFs and start codon selection stringency.

Thomas E Dever1, Ivaylo P Ivanov1, Alan G Hinnebusch1

  • 1Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA thomas.dever@nih.gov ivaylo.ivanov@nih.gov ahinnebusch@nih.gov.

Genes & Development
|July 11, 2023
PubMed
Summary
This summary is machine-generated.

Upstream open reading frames (uORFs) regulate gene expression by controlling the translation of main open reading frames (mORFs). This review explores how uORFs can repress or stimulate translation, focusing on ribosome queuing and alternatives to the delayed reinitiation model.

Keywords:
ATF4GCN4eIF2 phosphorylationribosome queuingstringencyuORF

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Area of Science:

  • Molecular Biology
  • Genetics
  • Gene Regulation

Background:

  • Eukaryotic messenger RNAs (mRNAs) often contain upstream open reading frames (uORFs) preceding the main protein-coding sequence (mORF).
  • While typically inhibitory, uORFs play a crucial role in modulating the translation efficiency of the mORF.
  • Understanding uORF function is key to deciphering complex gene expression control.

Purpose of the Study:

  • To review the diverse mechanisms by which uORFs regulate mRNA translation.
  • To highlight the role of ribosome queuing in uORF-mediated translational repression.
  • To critically assess emerging models for uORF regulation, contrasting them with established theories like delayed reinitiation.

Main Methods:

  • Literature review and synthesis of existing research on uORF function.
  • Analysis of experimental evidence supporting different regulatory models.
  • Comparative evaluation of proposed mechanisms for uORF-mediated translational control.

Main Results:

  • uORFs exhibit dual roles, capable of both repressing and stimulating mORF translation.
  • Ribosome queuing is a significant mechanism contributing to translational repression by uORFs.
  • Recent findings challenge the universality of the delayed reinitiation model for uORF regulation, particularly for GCN4/ATF4 mRNAs.

Conclusions:

  • uORFs are versatile regulators of gene expression with context-dependent effects.
  • Ribosome queuing offers a mechanistic explanation for uORF-mediated repression.
  • Further research is needed to fully elucidate the alternative models of uORF regulation and their implications.