scholarly journals Cotranslational microRNA mediated messenger RNA destabilization

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Trinh To Tat ◽  
Patricia A Maroney ◽  
Sangpen Chamnongpol ◽  
Jeff Coller ◽  
Timothy W Nilsen
Keyword(s):  
Messenger Rna ◽  
Protein Production ◽  
Mrna Decay ◽  
Mrna Degradation ◽  
Free State ◽  
Biological Processes ◽  
Base Pairing ◽  
Considerable Evidence ◽  
Decay Model ◽  
Limited Base

MicroRNAs are small (22 nucleotide) regulatory molecules that play important roles in a wide variety of biological processes. These RNAs, which bind to targeted mRNAs via limited base pairing interactions, act to reduce protein production from those mRNAs. Considerable evidence indicates that miRNAs destabilize targeted mRNAs by recruiting enzymes that function in normal mRNA decay and mRNA degradation is widely thought to occur when mRNAs are in a ribosome free state. Nevertheless, when examined, miRNA targeted mRNAs are invariably found to be polysome associated; observations that appear to be at face value incompatible with a simple decay model. Here, we provide evidence that turnover of miRNA-targeted mRNAs occurs while they are being translated. Cotranslational mRNA degradation is initiated by decapping and proceeds 5’ to 3’ behind the last translating ribosome. These results provide an explanation for a long standing mystery in the miRNA field.

mRNA degradation and maturation in prokaryotes: the global players

2011 ◽  
Vol 2 (6) ◽  
pp. 491-506 ◽  
Author(s):  
Soumaya Laalami ◽  
Harald Putzer
Keyword(s):  
Protein Synthesis ◽  
Messenger Rna ◽  
Mrna Decay ◽  
Mrna Degradation ◽  
Mrna Turnover ◽  
Model Organisms ◽  
Translation Regulation ◽  
Ecological Niches ◽  
Rnase E ◽  
General Role

AbstractThe degradation of messenger RNA is of universal importance for controlling gene expression. It directly affects protein synthesis by modulating the amount of mRNA available for translation. Regulation of mRNA decay provides an efficient means to produce just the proteins needed and to rapidly alter patterns of protein synthesis. In bacteria, the half-lives of individual mRNAs can differ by as much as two orders of magnitude, ranging from seconds to an hour. Most of what we know today about the diverse mechanisms of mRNA decay and maturation in prokaryotes comes from studies of the two model organisms Escherichia coli and Bacillus subtilis. Their evolutionary distance provided a large picture of potential pathways and enzymes involved in mRNA turnover. Among them are three ribonucleases, two of which have been discovered only recently, which have a truly general role in the initiating events of mRNA degradation: RNase E, RNase J and RNase Y. Their enzymatic characteristics probably determine the strategies of mRNA metabolism in the organism in which they are present. These ribonucleases are coded, alone or in various combinations, in all prokaryotic genomes, thus reflecting how mRNA turnover has been adapted to different ecological niches throughout evolution.

When mRNA translation meets decay

2017 ◽  
Vol 45 (2) ◽  
pp. 339-351 ◽  
Author(s):  
Alicia A. Bicknell ◽  
Emiliano P. Ricci
Keyword(s):  
Mrna Stability ◽  
Messenger Rna ◽  
Mrna Decay ◽  
Mrna Translation ◽  
Mrna Degradation ◽  
Mrna Surveillance ◽  
Protein Output

Messenger RNA (mRNA) translation and mRNA degradation are important determinants of protein output, and they are interconnected. Previously, it was thought that translation of an mRNA, as a rule, prevents its degradation. mRNA surveillance mechanisms, which degrade mRNAs as a consequence of their translation, were considered to be exceptions to this rule. Recently, however, it has become clear that many mRNAs are degraded co-translationally, and it has emerged that codon choice, by influencing the rate of ribosome elongation, affects the rate of mRNA decay. In this review, we discuss the links between translation and mRNA stability, with an emphasis on emerging data suggesting that codon optimality may regulate mRNA degradation.

scholarly journals Dcp2 phosphorylation by Ste20 modulates stress granule assembly and mRNA decay in Saccharomyces cerevisiae

2010 ◽  
Vol 189 (5) ◽  
pp. 813-827 ◽  
Author(s):  
Je-Hyun Yoon ◽  
Eui-Ju Choi ◽  
Roy Parker
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Protein Interactions ◽  
Messenger Rna ◽  
Mrna Decay ◽  
Control Point ◽  
Stress Granules ◽  
Mrna Degradation ◽  
Stress Granule ◽  
Granule Formation ◽  
P Bodies

Translation and messenger RNA (mRNA) degradation are important sites of gene regulation, particularly during stress where translation and mRNA degradation are reprogrammed to stabilize bulk mRNAs and to preferentially translate mRNAs required for the stress response. During stress, untranslating mRNAs accumulate both in processing bodies (P-bodies), which contain some translation repressors and the mRNA degradation machinery, and in stress granules, which contain mRNAs stalled in translation initiation. How signal transduction pathways impinge on proteins modulating P-body and stress granule formation and function is unknown. We show that during stress in Saccharomyces cerevisiae, Dcp2 is phosphorylated on serine 137 by the Ste20 kinase. Phosphorylation of Dcp2 affects the decay of some mRNAs and is required for Dcp2 accumulation in P-bodies and specific protein interactions of Dcp2 and for efficient formation of stress granules. These results demonstrate that Ste20 has an unexpected role in the modulation of mRNA decay and translation and that phosphorylation of Dcp2 is an important control point for mRNA decapping.

scholarly journals The crucial roles of N6-methyladenosine (m6A) modification in the carcinogenesis and progression of colorectal cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Zhihao Fang ◽  
Yiqiu Hu ◽  
Jinhui Hu ◽  
Yanqin Huang ◽  
Shu Zheng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Nuclear Export ◽  
Messenger Rna ◽  
Regulatory Proteins ◽  
Biological Processes ◽  
The Past ◽  
Common Cancer ◽  
Potential Applications ◽  
Regulated Gene Expression

AbstractAs the predominant modification in RNA, N6-methyladenosine (m6A) has attracted increasing attention in the past few years since it plays vital roles in many biological processes. This chemical modification is dynamic, reversible and regulated by several methyltransferases, demethylases and proteins that recognize m6A modification. M6A modification exists in messenger RNA and affects their splicing, nuclear export, stability, decay, and translation, thereby modulating gene expression. Besides, the existence of m6A in noncoding RNAs (ncRNAs) could also directly or indirectly regulated gene expression. Colorectal cancer (CRC) is a common cancer around the world and of high mortality. Increasing evidence have shown that the changes of m6A level and the dysregulation of m6A regulatory proteins have been implicated in CRC carcinogenesis and progression. However, the underlying regulation laws of m6A modification to CRC remain elusive and better understanding of these mechanisms will benefit the diagnosis and therapy. In the present review, the latest studies about the dysregulation of m6A and its regulators in CRC have been summarized. We will focus on the crucial roles of m6A modification in the carcinogenesis and development of CRC. Moreover, we will also discuss the potential applications of m6A modification in CRC diagnosis and therapeutics.

MicroRNAs: Key Regulators in Lung Cancer

MicroRNA ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Younes El Founini ◽  
Imane Chaoui ◽  
Hind Dehbi ◽  
Mohammed El Mzibri ◽  
Roger Abounader ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Messenger Rna ◽  
Recent Literature ◽  
Immune Surveillance ◽  
Rna Stability ◽  
Noncoding Rnas ◽  
Therapy Resistance ◽  
Biological Processes ◽  
Genome Wide ◽  
Stable Forms

: Noncoding RNAs have emerged as key regulators of the genome upon gene expression profiling and genome-wide sequencing. Among these noncoding RNAs, microRNAs are short noncoding RNAs that regulate a plethora of functions, biological processes and human diseases by targeting the messenger RNA stability through 3’UTR binding, leading to either mRNA cleavage or translation repression, depending on microRNA-mRNA complementarity degree. Additionally, strong evidence has suggested that dysregulation of miRNAs contribute to the etiology and progression of human cancers, such as lung cancer, the most common and deadliest cancer worldwide. Indeed, by acting as oncogenes or tumor suppressors, microRNAs control all aspects of lung cancer malignancy, including cell proliferation, survival, migration, invasion, angiogenesis, cancer stem cells, immune-surveillance escape, and therapy resistance; and their expressions are often associated with clinical parameters. Moreover, several deregulated microRNAs in lung cancer are carried by exosomes, microvesicles and secreted in body fluids, mainly the circulation where they conserve their stable forms. Subsequently, seminal efforts have been focused on extracellular microRNAs levels as noninvasive diagnostic and prognostic biomarkers in lung cancer. In this review, focusing on recent literature, we summarize the deregulation, mechanisms of action, functions and highlight clinical applications of miRNAs for better management and design of future lung cancer targeted therapies.

scholarly journals Systems Analysis of Transcriptomic and Proteomic Profiles Identifies Novel Regulation of Fibrotic Programs by miRNAs in Pulmonary Fibrosis Fibroblasts

Genes ◽  
2018 ◽  
Vol 9 (12) ◽  
pp. 588 ◽  
Author(s):  
Steven Mullenbrock ◽  
Fei Liu ◽  
Suzanne Szak ◽  
Xiaoping Hronowski ◽  
Benbo Gao ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Systems Analysis ◽  
Messenger Rna ◽  
Protein Production ◽  
Lung Fibroblasts ◽  
Effector Cells ◽  
Signature Genes ◽  
Gene And Protein Expression ◽  
Lung Transplants ◽  
Generation Sequencing

Fibroblasts/myofibroblasts are the key effector cells responsible for excessive extracellular matrix (ECM) deposition and fibrosis progression in both idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc) patient lungs, thus it is critical to understand the transcriptomic and proteomic programs underlying their fibrogenic activity. We conducted the first integrative analysis of the fibrotic programming in these cells at the levels of gene and microRNA (miRNA) expression, as well as deposited ECM protein to gain insights into how fibrotic transcriptional programs culminate in aberrant ECM protein production/deposition. We identified messenger RNA (mRNA), miRNA, and deposited matrisome protein signatures for IPF and SSc fibroblasts obtained from lung transplants using next-generation sequencing and mass spectrometry. SSc and IPF fibroblast transcriptional signatures were remarkably similar, with enrichment of WNT, TGF-β, and ECM genes. miRNA-seq identified differentially regulated miRNAs, including downregulation of miR-29b-3p, miR-138-5p and miR-146b-5p in disease fibroblasts and transfection of their mimics decreased expression of distinct sets of fibrotic signature genes as assessed using a Nanostring fibrosis panel. Finally, proteomic analyses uncovered a distinct “fibrotic” matrisome profile deposited by IPF and SSc fibroblasts compared to controls that highlights the dysregulated ECM production underlying their fibrogenic activities. Our comprehensive analyses of mRNA, miRNA, and matrisome proteomic profiles in IPF and SSc lung fibroblasts revealed robust fibrotic signatures at both the gene and protein expression levels and identified novel fibrogenesis-associated miRNAs whose aberrant downregulation in disease fibroblasts likely contributes to their fibrotic and ECM gene expression.

mRNA degradation by processive 3′-5′ exoribonucleases in Vitro and the implications for prokaryotic mRNA decay in Vivo

1991 ◽  
Vol 221 (1) ◽  
pp. 81-95 ◽  
Author(s):  
Robert S. McLaren ◽  
Sarah F. Newbury ◽  
Geoffrey S.C. Dance ◽  
Helen C. Causton ◽  
Christopher F. Higgins
Keyword(s):  
Mrna Decay ◽  
Mrna Degradation

scholarly journals Synthesis of phosphoramidites of isoGNA, an isomer of glycerol nucleic acid

2014 ◽  
Vol 10 ◽  
pp. 2131-2138 ◽  
Author(s):  
Keunsoo Kim ◽  
Venkateshwarlu Punna ◽  
Phaneendrasai Karri ◽  
Ramanarayanan Krishnamurthy
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Structural Unit ◽  
Easy Access ◽  
Alternative Route ◽  
Base Pairing ◽  
Limited Base ◽  
Glycerol Nucleic Acid ◽  
Adenine Derivative

IsoGNA, an isomer of glycerol nucleic acid GNA, is a flexible (acyclic) nucleic acid with bases directly attached to its linear backbone. IsoGNA exhibits (limited) base-pairing properties which are unique compared to other known flexible nucleic acids. Herein, we report on the details of the preparation of isoGNA phosphoramidites and an alternative route for the synthesis of the adenine derivative. The synthetic improvements described here enable an easy access to isoGNA and allows for the further exploration of this structural unit in oligonucleotide chemistry thereby spurring investigations of its usefulness and applicability.

scholarly journals MOV10 facilitates messenger RNA decay in an N6-methyladenosine (m6A) dependent manner to maintain the mouse embryonic stem cells state

2021 ◽  
Author(s):  
Majid Mehravar ◽  
Yogesh Kumar ◽  
Moshe Olshansky ◽  
Dhiru Bansal ◽  
Craig Dent ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Cell Biology ◽  
Messenger Rna ◽  
Mrna Decay ◽  
Embryonic Stem ◽  
Mouse Embryonic Stem Cells ◽  
Beta Catenin ◽  
Dependent Manner ◽  
Leukaemia Virus

N6-methyladenosine (m6A) is the most predominant internal mRNA modification in eukaryotes, recognised by its reader proteins (so-called m6A-readers) for regulating subsequent mRNA fates, such as splicing, export, localisation, decay, stability, and translation to control several biological processes. Although a few m6A-readers have been identified, yet the list is incomplete. Here, we identify a new m6A-reader protein, Moloney leukaemia virus 10 homologue (MOV10), in mouse embryonic stem cells (mESCs). MOV10 recognises m6A-containing mRNAs with a conserved GGm6ACU motif. Mechanistic studies uncover that MOV10 facilitates mRNA decay of its bound m6A- containing mRNAs in an m6A-dependent manner within the cytoplasmic processing bodies (P-bodies). Furthermore, MOV10 decays the Gsk-3beta mRNA through m6A that stabilises the BETA-CATENIN expression of a WNT/BETA-CATENIN signalling pathway to regulate downstream NANOG expression for maintaining the mESC state. Thus, our findings reveal how a newly identified m6A-reader, MOV10 mediates mRNA decay via m6A that impact embryonic stem cell biology.

scholarly journals Selective inhibition of the p38α MAPK–MK2 axis inhibits inflammatory cues including inflammasome priming signals

2018 ◽  
Vol 215 (5) ◽  
pp. 1315-1325 ◽  
Author(s):  
Chun Wang ◽  
Susan Hockerman ◽  
E. Jon Jacobsen ◽  
Yael Alippe ◽  
Shaun R. Selness ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Clinical Trials ◽  
Mrna Decay ◽  
Selective Inhibition ◽  
Mrna Degradation ◽  
Cytokine Expression ◽  
Clinical Translation ◽  
Tnf Α ◽  
P38α Mapk ◽  
Nlrp3 Expression

p38α activation of multiple effectors may underlie the failure of global p38α inhibitors in clinical trials. A unique inhibitor (CDD-450) was developed that selectively blocked p38α activation of the proinflammatory kinase MK2 while sparing p38α activation of PRAK and ATF2. Next, the hypothesis that the p38α–MK2 complex mediates inflammasome priming cues was tested. CDD-450 had no effect on NLRP3 expression, but it decreased IL-1β expression by promoting IL-1β mRNA degradation. Thus, IL-1β is regulated not only transcriptionally by NF-κB and posttranslationally by the inflammasomes but also posttranscriptionally by p38α–MK2. CDD-450 also accelerated TNF-α and IL-6 mRNA decay, inhibited inflammation in mice with cryopyrinopathy, and was as efficacious as global p38α inhibitors in attenuating arthritis in rats and cytokine expression by cells from patients with cryopyrinopathy and rheumatoid arthritis. These findings have clinical translation implications as CDD-450 offers the potential to avoid tachyphylaxis associated with global p38α inhibitors that may result from their inhibition of non-MK2 substrates involved in antiinflammatory and housekeeping responses.

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