scholarly journals Ribosome reinitiation can explain length-dependent translation of messenger RNA

2017 ◽  
Author(s):  
David W. Rogers ◽  
Marvin A. Böettcher ◽  
Arne Traulsen ◽  
Duncan Greig
Keyword(s):  
Protein Synthesis ◽  
Negative Correlation ◽  
Messenger Rna ◽  
Linear Models ◽  
Mrna Translation ◽  
Mechanistic Explanation ◽  
Eukaryotic Translation ◽  
Transcript Length ◽  
Eukaryotic Mrnas ◽  
Time Required

AbstractModels of mRNA translation usually presume that transcripts are linear; upon reaching the end of a transcript each terminating ribosome returns to the cytoplasmic pool before initiating anew on a different transcript. A consequence of linear models is that faster translation of a given mRNA is unlikely to generate more of the encoded protein, particularly at low ribosome availability. Recent evidence indicates that eukaryotic mRNAs are circularized, potentially allowing terminating ribosomes to preferentially reinitiate on the same transcript. Here we model the effect of ribosome reinitiation on translation and show that, at high levels of reinitiation, protein synthesis rates are dominated by the time required to translate a given transcript. Our model provides a simple mechanistic explanation for many previously enigmatic features of eukaryotic translation, including the negative correlation of both ribosome densities and protein abundance on transcript length, the importance of codon usage in determining protein synthesis rates, and the negative correlation between transcript length and both codon adaptation and 5' mRNA folding energies. In contrast to linear models where translation is largely limited by initiation rates, our model reveals that all three stages of translation - initiation, elongation, and termination/reinitiation - determine protein synthesis rates even at low ribosome availability.

scholarly journals Protein synthesis in the dendrite

2002 ◽  
Vol 357 (1420) ◽  
pp. 521-529 ◽  
Author(s):  
Shao Jun Tang ◽  
Erin M. Schuman
Keyword(s):  
Protein Synthesis ◽  
Neural Plasticity ◽  
Messenger Rna ◽  
Mrna Translation ◽  
Synaptic Activity ◽  
Synaptic Proteins ◽  
Local Source ◽  
Synaptic Protein ◽  
Specific Proteins ◽  
Molecular Nature

In neurons, many proteins that are involved in the transduction of synaptic activity and the expression of neural plasticity are specifically localized at synapses. How these proteins are targeted is not clearly understood. One mechanism is synaptic protein synthesis. According to this idea, messenger RNA (mRNA) translation from the polyribosomes that are observed at the synaptic regions provides a local source of synaptic proteins. Although an increasing number of mRNA species has been detected in the dendrite, information about the synaptic synthesis of specific proteins in a physiological context is still limited. The physiological function of synaptic synthesis of specific proteins in synaptogenesis and neural plasticity expression remains to be shown. Experiments aimed at understanding the mechanisms and functions f synaptic protein synthesis might provide important information about the molecular nature of neural plasticity.

scholarly journals eIF-Three to Tango: emerging functions of translation initiation factor eIF3 in protein synthesis and disease

2020 ◽  
Vol 12 (6) ◽  
pp. 403-409 ◽  
Author(s):  
Dieter A Wolf ◽  
Yingying Lin ◽  
Haoran Duan ◽  
Yabin Cheng
Keyword(s):  
Protein Synthesis ◽  
Messenger Rna ◽  
Protein Production ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Protein Homeostasis ◽  
Subcellular Targeting ◽  
Post Translational Modifications ◽  
The Past

Abstract Studies over the past three years have substantially expanded the involvements of eukaryotic initiation factor 3 (eIF3) in messenger RNA (mRNA) translation. It now appears that this multi-subunit complex is involved in every possible form of mRNA translation, controlling every step of protein synthesis from initiation to elongation, termination, and quality control in positive as well as negative fashion. Through the study of eIF3, we are beginning to appreciate protein synthesis as a highly integrated process coordinating protein production with protein folding, subcellular targeting, and degradation. At the same time, eIF3 subunits appear to have specific functions that probably vary between different tissues and individual cells. Considering the broad functions of eIF3 in protein homeostasis, it comes as little surprise that eIF3 is increasingly implicated in major human diseases and first attempts at therapeutically targeting eIF3 have been undertaken. Much remains to be learned, however, about subunit- and tissue-specific functions of eIF3 in protein synthesis and disease and their regulation by environmental conditions and post-translational modifications.

scholarly journals Regulation of mRNA translation in renal physiology and disease

2009 ◽  
Vol 297 (5) ◽  
pp. F1153-F1165 ◽  
Author(s):  
Balakuntalam S. Kasinath ◽  
Denis Feliers ◽  
Kavithalakshmi Sataranatarajan ◽  
Goutam Ghosh Choudhury ◽  
Myung Ja Lee ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Protein Synthesis ◽  
Messenger Rna ◽  
Kidney Injury ◽  
Mrna Translation ◽  
Renal Physiology ◽  
Physiological Adaptation ◽  
Three Stages ◽  
A Site

Translation, a process of generating a peptide from the codons present in messenger RNA, can be a site of independent regulation of protein synthesis; it has not been well studied in the kidney. Translation occurs in three stages (initiation, elongation, and termination), each with its own set of regulatory factors. Mechanisms controlling translation include small inhibitory RNAs such as microRNAs, binding proteins, and signaling reactions. Role of translation in renal injury in diabetes, endoplasmic reticulum stress, acute kidney injury, and, in physiological adaptation to loss of nephrons is reviewed here. Contribution of mRNA translation to physiology and disease is not well understood. Because it is involved in such diverse areas as development and cancer, it should prove a fertile field for investigation in renal science.

Regulation of Protein Synthesis by eIF4E in the Brain

2020 ◽  
Author(s):  
Kleanthi Chalkiadaki ◽  
Stella Kouloulia ◽  
Clive R. Bramham ◽  
Christos G. Gkogkas
Keyword(s):  
Protein Synthesis ◽  
Brain Function ◽  
Regulation Of Gene Expression ◽  
Mrna Translation ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Eukaryotic Mrnas ◽  
Rate Limiting ◽  
The Brain ◽  
Key Pathways

Regulation of gene expression at the level of mRNA translation is crucial for all the functions our brains carry out. eIF4E binds to the 5′-end of eukaryotic mRNAs and dictates the rate-limiting step of cap-dependent initiation. This chapter reviews the key pathways regulating eIF4E function, but also the less studied and novel mechanisms of eIF4E modulation, linked to synaptic plasticity, learning and memory, and nervous system disorders. Understanding how regulation of protein synthesis by eIF4E affects different aspects of brain function is yet elusive.

Translational control of the cdc25 cell cycle phosphatase: a molecular mechanism coupling mitosis to cell growth

1999 ◽  
Vol 112 (18) ◽  
pp. 3137-3146 ◽  
Author(s):  
R.R. Daga ◽  
J. Jimenez
Keyword(s):  
Protein Synthesis ◽  
Translation Initiation ◽  
Translational Control ◽  
Cell Mass ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation ◽  
Eukaryotic Mrnas ◽  
Eukaryotic Translation Initiation ◽  
Yeast Mutants

The eukaryotic translation initiation factor 4A (eIF4A) is an RNA helicase required for translation initiation of eukaryotic mRNAs. By engineering fission yeast mutants with diminished eIF4A activity, we have found that translation of cdc25 mRNAs (a dosage-dependent activator of mitosis in all eukaryotic cells) is particularly sensitive to limitations of protein synthesis mediated by limited eIF4A activity. Genetic and biochemical analysis indicated that a rate-limited translation initiation of cdc25 mRNAs, exerted throughout its unusual 5′ untranslated leader, acts as a molecular sensor to ensure that a minimum cell mass (protein synthesis) is attained before mitosis occurs. The Cdc13 cyclin B is also among the limited pool of proteins whose translation is sensitive to reduced translation initiation activity. Interestingly, the 5′ leader sequences of cdc25 and cdc13 mRNAs have conserved features which are unusual in other yeast mRNAs, suggesting that common mechanisms operate in the expression of these two key mitotic activators at the translational level.

scholarly journals Novel N7-Arylmethyl Substituted Dinucleotide mRNA 5′ cap Analogs: Synthesis and Evaluation as Modulators of Translation

Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1941
Author(s):  
Radoslaw Wojcik ◽  
Marek R. Baranowski ◽  
Lukasz Markiewicz ◽  
Dorota Kubacka ◽  
Marcelina Bednarczyk ◽  
...  
Keyword(s):  
Messenger Rna ◽  
A549 Cells ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation ◽  
Potential Applications ◽  
Eukaryotic Translation Initiation ◽  
Translational Inhibition

Dinucleotide analogs of the messenger RNA cap (m7GpppN) are useful research tools and have potential applications as translational inhibitors or reagents for modification of in vitro transcribed mRNAs. It has been previously reported that replacing the methyl group at the N7-position with benzyl (Bn) produces a dinucleotide cap with superior properties. Here, we followed up on this finding by synthesizing 17 novel Bn7GpppG analogs and determining their structure–activity relationship regarding translation and translational inhibition. The compounds were prepared in two steps, including selective N7-alkylation of guanosine 5′-monophosphate by arylmethyl bromide followed by coupling with imidazole-activated GDP, with total yields varying from 22% to 62%. The compounds were then evaluated by determining their affinity for eukaryotic translation initiation factor 4E (eIF4E), testing their susceptibility to decapping pyrophosphatase, DcpS—which is most likely the major cellular enzyme targeting this type of compound—and determining their translation inhibitory properties in vitro. We also synthesized mRNAs capped with the evaluated compounds and tested their translational properties in A549 cells. Our studies identified N7-(4-halogenbenzyl) substituents as promising modifications in the contexts of either mRNA translation or translational inhibition. Finally, to gain more insight into the consequences at the molecular level of N7-benzylation of the mRNA cap, we determined the crystal structures of three compounds with eIF4E.

scholarly journals Genetic removal of p70 S6K1 corrects coding sequence length-dependent alterations in mRNA translation in fragile X syndrome mice

2021 ◽  
Vol 118 (18) ◽  
pp. e2001681118
Author(s):  
Sameer Aryal ◽  
Francesco Longo ◽  
Eric Klann
Keyword(s):  
Protein Synthesis ◽  
Fragile X Syndrome ◽  
Messenger Rna ◽  
Fragile X ◽  
Mrna Translation ◽  
Ribosome Profiling ◽  
Sequence Length ◽  
Double Knockout ◽  
Coding Sequence ◽  
Mental Retardation Protein

Loss of the fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS). FMRP is widely thought to repress protein synthesis, but its translational targets and modes of control remain in dispute. We previously showed that genetic removal of p70 S6 kinase 1 (S6K1) corrects altered protein synthesis as well as synaptic and behavioral phenotypes in FXS mice. In this study, we examined the gene specificity of altered messenger RNA (mRNA) translation in FXS and the mechanism of rescue with genetic reduction of S6K1 by carrying out ribosome profiling and RNA sequencing on cortical lysates from wild-type, FXS, S6K1 knockout, and double knockout mice. We observed reduced ribosome footprint (RF) abundance in the majority of differentially translated genes in the cortices of FXS mice. We used molecular assays to discover evidence that the reduction in RF abundance reflects an increased rate of ribosome translocation, which is captured as a decrease in the number of translating ribosomes at steady state and is normalized by inhibition of S6K1. We also found that genetic removal of S6K1 prevented a positive-to-negative gradation of alterations in translation efficiencies (RF/mRNA) with coding sequence length across mRNAs in FXS mouse cortices. Our findings reveal the identities of dysregulated mRNAs and a molecular mechanism by which reduction of S6K1 prevents altered translation in FXS.

scholarly journals Translational control by RGS2

2009 ◽  
Vol 186 (5) ◽  
pp. 755-765 ◽  
Author(s):  
Chau H. Nguyen ◽  
Hong Ming ◽  
Peishen Zhao ◽  
Lynne Hugendubler ◽  
Robert Gros ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
G Protein ◽  
Translational Control ◽  
Messenger Rna ◽  
Mrna Translation ◽  
Initiation Factor ◽  
Rgs Proteins ◽  
Rgs Domain ◽  
Guanosine Triphosphatase ◽  
Gtpase Cycle

The regulator of G protein signaling (RGS) proteins are a family of guanosine triphosphatase (GTPase)–accelerating proteins. We have discovered a novel function for RGS2 in the control of protein synthesis. RGS2 was found to bind to eIF2Bε (eukaryotic initiation factor 2B ε subunit) and inhibit the translation of messenger RNA (mRNA) into new protein. This effect was not observed for other RGS proteins tested. This novel function of RGS2 is distinct from its ability to regulate G protein–mediated signals and maps to a stretch of 37 amino acid residues within its conserved RGS domain. Moreover, RGS2 was capable of interfering with the eIF2–eIF2B GTPase cycle, which is a requisite step for the initiation of mRNA translation. Collectively, this study has identified a novel role for RGS2 in the control of protein synthesis that is independent of its established RGS domain function.

Focusing on mRNA Granules and Stalled Polysomes Amidst Diverse Mechanisms Underlying mRNA Transport, mRNA Storage, and Local Translation

2020 ◽  
Author(s):  
Mina N. Anadolu ◽  
Wayne S. Sossin
Keyword(s):  
Protein Synthesis ◽  
Liquid Phase ◽  
Mrna Translation ◽  
Rna Transport ◽  
P Bodies ◽  
Rna Granules ◽  
Mrna Granules ◽  
Transport Particle ◽  
As Stress ◽  
The Individual

In neurons, mRNAs are transported to distal sites to allow for localized protein synthesis. There are many diverse mechanisms underlying this transport. For example, an individual mRNA can be transported in an RNA transport particle that is tailored to the individual mRNA and its associated binding proteins. In contrast, some mRNAs are transported in liquid-liquid phase separated structures called neuronal RNA granules that are made up of multiple stalled polysomes, allowing for rapid initiation-independent production of proteins required for synaptic plasticity. Moreover, neurons have additional types of liquid-liquid phase–separated structures containing mRNA, such as stress granules and P bodies. This chapter discusses the relationships between all of these structures, what proteins distinguish them, and the possible roles they play in the complex control of mRNA translation at distal sites that allow neurons to use protein synthesis to refine their local proteome in many different ways.

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