Regulation of 7B2 mRNA Translation: Dissecting the Role of Its 5′-Untranslated Region

AbstractFTO removes the N6-methyladenosine (m6A) modification from genes and plays a critical role in cancer development. However, the mechanisms underlying the regulation of FTO and its subsequent impact on the regulation of the epitranscriptome remain to be further elucidated. Here, we demonstrate that FTO expression is downregulated and inversely correlated with poor survival of lung adenocarcinoma patients. Mechanistically, Wnt signaling induces the binding of EZH2 to β-catenin. This protein complex binds to the LEF/TCF-binding elements at the promoter region of FTO, where EZH2 enhances H3K27me3 and inhibits FTO expression. Downregulated FTO expression substantially enhances the m6A levels in the mRNAs of a large number of genes in critical pathways, particularly metabolic pathway genes, such as MYC. Enhanced m6A levels on MYC mRNA recruit YTHDF1 binding, which promotes MYC mRNA translation and a subsequent increase in glycolysis and proliferation of tumor cells and tumorigenesis. Our findings uncovered a critical mechanism of epitranscriptome regulation by Wnt/β-catenin-mediated FTO downregulation and underscored the role of m6A modifications of MYC mRNA in regulating tumor cell glycolysis and growth.

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The Role of Translation Initiation Regulation in Haematopoiesis

Comparative and Functional Genomics ◽

10.1155/2012/576540 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 7

Author(s):

Godfrey Grech ◽

Marieke von Lindern

Keyword(s):

Gene Expression ◽

Translation Initiation ◽

Translational Control ◽

Molecular Mechanisms ◽

Rna Binding ◽

Regulation Of Gene Expression ◽

Mrna Translation ◽

Translation Control ◽

Haematological Disorders

Organisation of RNAs into functional subgroups that are translated in response to extrinsic and intrinsic factors underlines a relatively unexplored gene expression modulation that drives cell fate in the same manner as regulation of the transcriptome by transcription factors. Recent studies on the molecular mechanisms of inflammatory responses and haematological disorders indicate clearly that the regulation of mRNA translation at the level of translation initiation, mRNA stability, and protein isoform synthesis is implicated in the tight regulation of gene expression. This paper outlines how these posttranscriptional control mechanisms, including control at the level of translation initiation factors and the role of RNA binding proteins, affect hematopoiesis. The clinical relevance of these mechanisms in haematological disorders indicates clearly the potential therapeutic implications and the need of molecular tools that allow measurement at the level of translational control. Although the importance of miRNAs in translation control is well recognised and studied extensively, this paper will exclude detailed account of this level of control.

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4E-BP2–dependent translation in parvalbumin neurons controls epileptic seizure threshold

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2025522118 ◽

2021 ◽

Vol 118 (15) ◽

pp. e2025522118

Author(s):

Vijendra Sharma ◽

Rapita Sood ◽

Danning Lou ◽

Tzu-Yu Hung ◽

Maxime Lévesque ◽

...

Keyword(s):

Animal Models ◽

Mammalian Target Of Rapamycin ◽

Neuronal Cell ◽

Mrna Translation ◽

Translation Initiation Factor ◽

Inhibitory Neurons ◽

Initiation Factor ◽

Seizure Threshold ◽

Parvalbumin Neurons

The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) integrates multiple signals to regulate critical cellular processes such as mRNA translation, lipid biogenesis, and autophagy. Germline and somatic mutations in mTOR and genes upstream of mTORC1, such as PTEN, TSC1/2, AKT3, PIK3CA, and components of GATOR1 and KICSTOR complexes, are associated with various epileptic disorders. Increased mTORC1 activity is linked to the pathophysiology of epilepsy in both humans and animal models, and mTORC1 inhibition suppresses epileptogenesis in humans with tuberous sclerosis and animal models with elevated mTORC1 activity. However, the role of mTORC1-dependent translation and the neuronal cell types mediating the effect of enhanced mTORC1 activity in seizures remain unknown. The eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and 2 (4E-BP2) are translational repressors downstream of mTORC1. Here we show that the ablation of 4E-BP2, but not 4E-BP1, in mice increases the sensitivity to pentylenetetrazole (PTZ)- and kainic acid (KA)–induced seizures. We demonstrate that the deletion of 4E-BP2 in inhibitory, but not excitatory neurons, causes an increase in the susceptibility to PTZ-induced seizures. Moreover, mice lacking 4E-BP2 in parvalbumin, but not somatostatin or VIP inhibitory neurons exhibit a lowered threshold for seizure induction and reduced number of parvalbumin neurons. A mouse model harboring a human PIK3CA mutation that enhances the activity of the PI3K-AKT pathway (Pik3caH1047R-Pvalb) selectively in parvalbumin neurons shows susceptibility to PTZ-induced seizures. Our data identify 4E-BP2 as a regulator of epileptogenesis and highlight the central role of increased mTORC1-dependent translation in parvalbumin neurons in the pathophysiology of epilepsy.

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METTL3 Intensifies the Progress of Oral Squamous Cell Carcinoma via Modulating the m6A Amount of PRMT5 and PD-L1

Journal of Immunology Research ◽

10.1155/2021/6149558 ◽

2021 ◽

Vol 2021 ◽

pp. 1-15

Author(s):

Yilong Ai ◽

Shiwei Liu ◽

Hailing Luo ◽

Siyuan Wu ◽

Haigang Wei ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Mrna Translation ◽

Qrt Pcr ◽

Methylation Assay ◽

Eukaryotic Mrnas ◽

M6a Rna Methylation

N6-Methyladenosine (m6A) modification is one of the commonest chemical modifications in eukaryotic mRNAs, which has essential effects on mRNA translation, splicing, and stability. Currently, there is a rising concern on the regulatory role of m6A in tumorigenesis. As a known component in the m6A methyltransferase complex, METTL3 (methyltransferase-like 3) plays an essential role in m6A methylation. Till now, the functions of METTL3 in oral squamous cell carcinoma (OSCC) and its relative mechanism remain to be explored. In this research, through the GEPIA database, we found that high METTL3 expression has a correlation with poor prognosis of squamous cell carcinoma of head and neck. qRT-PCR displayed that METTL3 was highly expressed in OSCC cells. Functionally, METTL3 knockdown reduced the invasion, migration, and proliferation competence of OSCC cells and attenuated the activation of CD8+ T cells. In contrast, METTL3 overexpression resulted in opposite results. GEPIA, UALCAN, and SRAMP databases, PCR, western blot, and m6A RNA methylation assay confirmed the m6A modification of PRMT5 and PD-L1 mediated by METTL3. In conclusion, our results displayed that METTL3 intensified the metastasis and proliferation of OSCC by modulating the m6A amounts of PRMT5 and PD-L1, suggesting that METTL3 may be a therapeutic target for OSCC patients.

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CircRNAs and their regulatory roles in cancers

Molecular Medicine ◽

10.1186/s10020-021-00359-3 ◽

2021 ◽

Vol 27 (1) ◽

Author(s):

Mei Tao ◽

Ming Zheng ◽

Yanhua Xu ◽

Shuo Ma ◽

Weiwei Zhang ◽

...

Keyword(s):

Nuclear Export ◽

Mrna Translation ◽

High Sensitivity ◽

Detection Methods ◽

Circular Rnas ◽

Rnase L ◽

Circular Structure ◽

Dynamic Modification ◽

Non Coding Rnas

AbstractCircular RNAs (circRNAs), a novel type of non-coding RNAs (ncRNAs), have a covalently closed circular structure resulting from pre-mRNA back splicing via spliceosome and ribozymes. They can be classified differently in accordance with different criteria. As circRNAs are abundant, conserved, and stable, they can be used as diagnostic markers in various diseases and targets to develop new therapies. There are various functions of circRNAs, including sponge for miR/proteins, role of scaffolds, templates for translation, and regulators of mRNA translation and stability. Without m7G cap and poly-A tail, circRNAs can still be degraded in several ways, including RNase L, Ago-dependent, and Ago-independent degradation. Increasing evidence indicates that circRNAs can be modified by N-6 methylation (m6A) in many aspects such as biogenesis, nuclear export, translation, and degradation. In addition, they have been proved to play a regulatory role in the progression of various cancers. Recently, methods of detecting circRNAs with high sensitivity and specificity have also been reported. This review presents a detailed overview of circRNAs regarding biogenesis, biomarker, functions, degradation, and dynamic modification as well as their regulatory roles in various cancers. It’s particularly summarized in detail in the biogenesis of circRNAs, regulation of circRNAs by m6A modification and mechanisms by which circRNAs affect tumor progression respectively. Moreover, existing circRNA detection methods and their characteristics are also mentioned.

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The 5′ Untranslated Region of the Major Immediate Early mRNA Is Necessary for Efficient Human Cytomegalovirus Replication

Journal of Virology ◽

10.1128/jvi.02128-17 ◽

2018 ◽

Vol 92 (7) ◽

Cited By ~ 6

Author(s):

Kyle C. Arend ◽

Erik M. Lenarcic ◽

Nathaniel J. Moorman

Keyword(s):

Protein Expression ◽

Human Cytomegalovirus ◽

Untranslated Region ◽

Mrna Translation ◽

Lytic Replication ◽

Immediate Early ◽

Translation Control ◽

Positive Role ◽

Free System ◽

Hcmv Replication

ABSTRACTThe human cytomegalovirus (HCMV) immediate early 1 (IE1) and IE2 proteins are critical regulators of virus replication. Both proteins are needed to efficiently establish lytic infection, and nascent expression of IE1 and IE2 is critical for reactivation from latency. The regulation of IE1 and IE2 protein expression is thus a central event in the outcome of HCMV infection. Transcription of the primary transcript encoding both IE1 and IE2 is well studied, but relatively little is known about the posttranscriptional mechanisms that control IE1 and IE2 protein synthesis. The mRNA 5′ untranslated region (5′ UTR) plays an important role in regulating mRNA translation. Therefore, to better understand the control of IE1 and IE2 mRNA translation, we examined the role of the shared 5′ UTR of the IE1 and IE2 mRNAs (MIE 5′ UTR) in regulating translation. In a cell-free system, the MIE 5′ UTR repressed translation, as predicted based on its length and sequence composition. However, in transfected cells we found that the MIE 5′ UTR increased the expression of a reporter gene and enhanced its association with polysomes, demonstrating that the MIE 5′ UTR has a positive role in translation control. We also found that the MIE 5′ UTR was necessary for efficient IE1 and IE2 translation during infection. Replacing the MIE 5′ UTR with an unstructured sequence of the same length decreased IE1 and IE2 protein expression despite similar levels of IE1 and IE2 mRNA and reduced the association of the IE1 and IE2 mRNAs with polysomes. The wild-type MIE 5′-UTR sequence was also necessary for efficient HCMV replication. Together these data identify the shared 5′ UTR of the IE1 and IE2 mRNAs as an important regulator of HCMV lytic replication.IMPORTANCEThe HCMV IE1 and IE2 proteins are critical regulators of HCMV replication, both during primary infection and during reactivation from viral latency. Thus, defining factors that regulate IE1 and IE2 expression is important for understanding the molecular events controlling the HCMV replicative cycle. Here we identify a positive role for the MIE 5′ UTR in mediating the efficient translation of the IE1 and IE2 mRNAs. This result is an important advance for several reasons. To date, most studies of IE1 and IE2 regulation have focused on defining events that regulate IE1 and IE2 transcription. Our work reveals that in addition to the regulation of transcription, IE1 and IE2 are also regulated at the level of translation. Therefore, this study is important in that it identifies an additional layer of regulation controlling IE1 and IE2 expression and thus HCMV pathogenesis. These translational regulatory events could potentially be targeted by novel antiviral therapeutics that limit IE1 and IE2 mRNA translation and thus inhibit lytic replication or prevent HCMV reactivation.

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Apontic binds the translational repressor Bruno and is implicated in regulation of oskar mRNA translation

Development ◽

10.1242/dev.126.6.1129 ◽

1999 ◽

Vol 126 (6) ◽

pp. 1129-1138 ◽

Cited By ~ 1

Author(s):

Y.S. Lie ◽

P.M. Macdonald

Keyword(s):

Translational Control ◽

Untranslated Region ◽

Rna Binding ◽

Mrna Translation ◽

Posterior Pole ◽

Translational Repression ◽

Yeast Two Hybrid ◽

Functional Interaction ◽

Translational Repressor ◽

Two Hybrid

The product of the oskar gene directs posterior patterning in the Drosophila oocyte, where it must be deployed specifically at the posterior pole. Proper expression relies on the coordinated localization and translational control of the oskar mRNA. Translational repression prior to localization of the transcript is mediated, in part, by the Bruno protein, which binds to discrete sites in the 3′ untranslated region of the oskar mRNA. To begin to understand how Bruno acts in translational repression, we performed a yeast two-hybrid screen to identify Bruno-interacting proteins. One interactor, described here, is the product of the apontic gene. Coimmunoprecipitation experiments lend biochemical support to the idea that Bruno and Apontic proteins physically interact in Drosophila. Genetic experiments using mutants defective in apontic and bruno reveal a functional interaction between these genes. Given this interaction, Apontic is likely to act together with Bruno in translational repression of oskar mRNA. Interestingly, Apontic, like Bruno, is an RNA-binding protein and specifically binds certain regions of the oskar mRNA 3′ untranslated region.

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Stabilizing role of structural elements within the 5´ Untranslated Region (UTR) and gag sequences in Mason-Pfizer monkey virus (MPMV) genomic RNA packaging

RNA Biology ◽

10.1080/15476286.2019.1572424 ◽

2019 ◽

Vol 16 (5) ◽

pp. 612-625 ◽

Cited By ~ 1

Author(s):

Rawan M. Kalloush ◽

Valérie Vivet-Boudou ◽

Lizna M. Ali ◽

Vineeta N. Pillai ◽

Farah Mustafa ◽

...

Keyword(s):

Untranslated Region ◽

Structural Elements ◽

Genomic Rna ◽

Rna Packaging

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Mixed tailing by TENT4A and TENT4B shields mRNA from rapid deadenylation

Science ◽

10.1126/science.aam5794 ◽

2018 ◽

Vol 361 (6403) ◽

pp. 701-704 ◽

Cited By ~ 43

Author(s):

Jaechul Lim ◽

Dongwan Kim ◽

Young-suk Lee ◽

Minju Ha ◽

Mihye Lee ◽

...

Keyword(s):

Gene Regulation ◽

Half Life ◽

Messenger Rna ◽

Mrna Translation ◽

Posttranscriptional Gene Regulation ◽

And Function ◽

Mrna Half Life ◽

In Cells

RNA tails play integral roles in the regulation of messenger RNA (mRNA) translation and decay. Guanylation of the poly(A) tail was discovered recently, yet the enzymology and function remain obscure. Here we identify TENT4A (PAPD7) and TENT4B (PAPD5) as the enzymes responsible for mRNA guanylation. Purified TENT4 proteins generate a mixed poly(A) tail with intermittent non-adenosine residues, the most common of which is guanosine. A single guanosine residue is sufficient to impede the deadenylase CCR4-NOT complex, which trims the tail and exposes guanosine at the 3′ end. Consistently, depletion of TENT4A and TENT4B leads to a decrease in mRNA half-life and abundance in cells. Thus, TENT4A and TENT4B produce a mixed tail that shields mRNA from rapid deadenylation. Our study unveils the role of mixed tailing and expands the complexity of posttranscriptional gene regulation.

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