Mixed tailing by TENT4A and TENT4B shields mRNA from rapid deadenylation

Science ◽  
2018 ◽  
Vol 361 (6403) ◽  
pp. 701-704 ◽  
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.

scholarly journals Dynamic mRNA modifications: An emerging layer of gene regulation

2015 ◽  
Vol 37 (2) ◽  
pp. 14-18 ◽  
Author(s):  
Adrian Whitehouse
Keyword(s):  
Gene Regulation ◽  
Messenger Rna ◽  
Fine Tuning ◽  
Minor Role ◽  
Small Nuclear Rna ◽  
Non Coding Rna ◽  
A Minor ◽  
And Function ◽  
Long Non Coding Rna

More than 100 different types of chemical modifications are found in cellular RNAs, including ribosomal RNA (rRNA), transfer RNA (tRNA), messenger RNA (mRNA), long non-coding RNA (lncRNA) and small nuclear RNA (snRNA). Internal modifications of mRNA were first observed in the 1970s, but, until recently, the role of these mRNA modifications has been a largely neglected field. A long-standing view was that mRNA modifications were static and unalterable, having a minor role in fine-tuning the structure and function of mRNAs. However, recent exciting discoveries now suggest that certain mRNA modifications are dynamic and, in some cases, reversible. Therefore they may have critical regulatory roles in gene expression, analogous to those which dynamically regulate DNA and protein modifications. As such, understanding the scope and mechanisms of these dynamic mRNA modifications represents an emerging layer of gene regulation at the RNA level, termed epitranscriptomics or RNA epigenetics.

scholarly journals Roles of Elongator Dependent tRNA Modification Pathways in Neurodegeneration and Cancer

Genes ◽  
2018 ◽  
Vol 10 (1) ◽  
pp. 19 ◽  
Author(s):  
Harmen Hawer ◽  
Alexander Hammermeister ◽  
Keerthiraju Ravichandran ◽  
Sebastian Glatt ◽  
Raffael Schaffrath ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Disease ◽  
Messenger Rna ◽  
Environmental Changes ◽  
Mrna Translation ◽  
Regulatory Control ◽  
Trna Modification ◽  
Positive Role ◽  
Trna Modifications

Transfer RNA (tRNA) is subject to a multitude of posttranscriptional modifications which can profoundly impact its functionality as the essential adaptor molecule in messenger RNA (mRNA) translation. Therefore, dynamic regulation of tRNA modification in response to environmental changes can tune the efficiency of gene expression in concert with the emerging epitranscriptomic mRNA regulators. Several of the tRNA modifications are required to prevent human diseases and are particularly important for proper development and generation of neurons. In addition to the positive role of different tRNA modifications in prevention of neurodegeneration, certain cancer types upregulate tRNA modification genes to sustain cancer cell gene expression and metastasis. Multiple associations of defects in genes encoding subunits of the tRNA modifier complex Elongator with human disease highlight the importance of proper anticodon wobble uridine modifications (xm5U34) for health. Elongator functionality requires communication with accessory proteins and dynamic phosphorylation, providing regulatory control of its function. Here, we summarized recent insights into molecular functions of the complex and the role of Elongator dependent tRNA modification in human disease.

scholarly journals The role of micro-RNAs in the female reproductive tract

Reproduction ◽  
2012 ◽  
Vol 143 (5) ◽  
pp. 559-576 ◽  
Author(s):  
Warren B Nothnick
Keyword(s):  
Posttranslational Modifications ◽  
Reproductive Tract ◽  
Current Knowledge ◽  
Female Reproductive Tract ◽  
Micro Rna ◽  
Proper Function ◽  
Posttranscriptional Gene Regulation ◽  
Micro Rnas ◽  
And Function

Proper development and function of the female reproductive tract are essential for successful reproduction. Regulation of the differentiated functions of the organs that make up the female reproductive tract is well established to occur at multiple levels including transcription, translation, and posttranslational modifications. Micro-RNA (miRNA)-mediated posttranscriptional gene regulation has emerged as a fundamental mechanism controlling normal tissue development and function. Emerging evidence indicates that miRNAs are expressed within the organs of the female reproductive tract where they function to regulate cellular pathways necessary for proper function of these organs. In this review, the functional significance of miRNAs in the development and function of the organs of the female reproductive tract is discussed. Initial discussion focuses on the role of miRNAs in the development of the organs of the female reproductive tract highlighting recent studies that clearly demonstrate that mice with disrupted Dicer1 expression are sterile, fail to develop uterine glands, and have muted estrogen responsiveness. Next, emphasis moves to discussion on our current knowledge on the characterization of miRNA expression in each of the organs of the female reproductive tract. When possible, information is presented and discussed with respect to regulation, function, and/or functional targets of these miRNA within each specific organ of the female reproductive tract.

Role of unfolded protein response in genital malformation/damage of male mice induced by flutamide

2020 ◽  
Vol 39 (12) ◽  
pp. 1690-1699
Author(s):  
H Yu ◽  
K Wen ◽  
X Zhou ◽  
Y Zhang ◽  
Z Yan ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Messenger Rna ◽  
Hypoxia Inducible Factor ◽  
Reproductive Organs ◽  
Pregnant Mouse ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
And Function ◽  
Protein Response

The unfolded protein response (UPR) is one of a switch of autophagy and apoptosis, and the endoplasmic reticulum stress (ERS) which inducing UPR plays a role in the malformations caused by some genetic and environmental factors. Exposure to flutamide during pregnancy will also cause abnormalities in some male offspring reproductive organs such as cryptorchidism. In this study, after administered the pregnant mouse orally at a dose of 300 mg/kg body weight every day during gestational day (GD)12 to GD18, flutamide can not only caused hypospadias in the male mouse offspring but also damaged the morphology and function of their testis. And the expression of UPR-related genes and proteins, autophagy, apoptosis, and angiogenesis-related genes of the damaged/teratogenic testis and penis in the mice were investigated to determine the role of UPR in this model. It was found that flutamide activated maybe the Atg7-Atg3-Lc3 pathway through the UPR pathway, caused cells excessive autophagy and apoptosis, and inhibited the formation of penile and testicular blood vessels by activating UPR and affecting the messenger RNA level of vascular endothelial growth factor and hypoxia-inducible factor 1.

scholarly journals Impact of ABCC2 haplotypes on transcriptional and posttranscriptional gene regulation and function

2010 ◽  
Vol 11 (1) ◽  
pp. 25-34 ◽  
Author(s):  
S Laechelt ◽  
E Turrini ◽  
A Ruehmkorf ◽  
W Siegmund ◽  
I Cascorbi ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Posttranscriptional Gene Regulation ◽  
And Function

A Dictyostelium prespore-specific gene is transcriptionally repressed by DIF in vitro

Development ◽  
1988 ◽  
Vol 103 (3) ◽  
pp. 519-524 ◽  
Author(s):  
A.E. Early ◽  
J.G. Williams
Keyword(s):  
Half Life ◽  
Stalk Cell ◽  
Specific Gene ◽  
Transcriptional Level ◽  
Mrna Half Life ◽  
Spore Cell ◽  
Transcriptional Controls

One important role of DIF, the stalk cell-specific inducer of Dictyostelium, may be to divert cells from the spore cell pathway of differentiation. The D19 gene encodes an mRNA which is highly enriched in prespore over prestalk cells in the migratory slug. We show, using a mutant defective in DIF accumulation, that the concentration of D19, and several other prespore mRNA sequences, decreases in the presence of exogenous DIF. There is evidence that both transcriptional and post-transcriptional controls operate to regulate expression of these genes. We have performed in vitro nuclear transcription and mRNA half-life analyses, and find that DIF acts at the transcriptional level to repress the accumulation of the D19 mRNA.

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.

The epidermal keratinocyte as a model for the study of gene regulation and cell differentiation

1997 ◽  
Vol 77 (2) ◽  
pp. 397-424 ◽  
Author(s):  
R. L. Eckert ◽  
J. F. Crish ◽  
N. A. Robinson
Keyword(s):  
Gene Regulation ◽  
Current Knowledge ◽  
Keratinocyte Differentiation ◽  
Marker Genes ◽  
Epidermal Keratinocyte ◽  
Major Cell Type ◽  
Life Threatening ◽  
Exogenous Agents ◽  
And Function

The epidermis is a dynamic, continually renewing structure that provides the organism with a life-sustaining interface with the environment. The major cell type of the epidermis, the epidermal keratinocyte, undergoes a complex and carefully choreographed program of differentiation. Aberrations in this process result in the genesis of a variety of debilitating and life-threatening diseases. In the present paper, we discuss the keratinocyte differentiation program and the exogenous agents that regulate differentiation. We describe the marker genes that have been utilized to study the process of gene regulation in epidermis. We describe the keratin proteins and studies that have identified keratin mutations that cause epidermal disease. We present recent information on regulation of keratinocyte gene expression and attempt to summarize current knowledge on the role of transcription factors in this process. We also discuss the process of cornified envelope assembly and the structure and function of the proteins that are thought to be precursors of this structure.

scholarly journals MicroRNAs in skin and wound healing

2011 ◽  
Vol 43 (10) ◽  
pp. 543-556 ◽  
Author(s):  
Jaideep Banerjee ◽  
Yuk Cheung Chan ◽  
Chandan K. Sen
Keyword(s):  
Wound Healing ◽  
Gene Regulation ◽  
Skin Diseases ◽  
Mrna Degradation ◽  
Messenger Rnas ◽  
Skin Development ◽  
Rna Molecules ◽  
Posttranscriptional Gene Regulation

MicroRNAs (miRNAs) are small endogenous RNA molecules ∼22 nt in length. miRNAs are capable of posttranscriptional gene regulation by binding to their target messenger RNAs (mRNAs), leading to mRNA degradation or suppression of translation. miRNAs have recently been shown to play pivotal roles in skin development and are linked to various skin pathologies, cancer, and wound healing. This review focuses on the role of miRNAs in cutaneous biology, the various methods of miRNA modulation, and the therapeutic opportunities in treatment of skin diseases and wound healing.

scholarly journals DNA methylation directs polycomb-dependent 3D genome re- organisation in naive pluripotency

2019 ◽  
Author(s):  
Katy A McLaughlin ◽  
Ilya M Flyamer ◽  
John P Thomson ◽  
Heidi K Mjoseng ◽  
Ruchi Shukla ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Gene Regulation ◽  
Ground State ◽  
Embryonic Stem ◽  
Genome Organisation ◽  
Dna Hypomethylation ◽  
3D Genome ◽  
And Function

The DNA hypomethylation that occurs when embryonic stem cells (ESCs) are directed to the ground state of naive pluripotency by culturing in 2i conditions results in redistribution of polycomb (H3K27me3) away from its target loci. Here we demonstrate that 3D genome organisation is also altered in 2i. We found chromatin decompaction at polycomb target loci as well as loss of long-range polycomb interactions. By preventing DNA hypomethylation during the transition to the ground-state, we are able to restore the H3K27me3 distribution, and polycomb-mediated 3D genome organisation that is characteristic of primed ESCs grown in serum, to ESCs in 2i. However, these cells retain the functional characteristics of 2i ground state ESCs. Our findings demonstrate the central role of DNA methylation in shaping major aspects of 3D genome organisation but caution against assuming causal roles for the epigenome and 3D genome in gene regulation and function in ESCs.

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