Ribosomal tunnel and translation regulation

2010 ◽  
Vol 75 (13) ◽  
pp. 1501-1516 ◽  
Author(s):  
A. A. Bogdanov ◽  
N. V. Sumbatyan ◽  
A. V. Shishkina ◽  
V. V. Karpenko ◽  
G. A. Korshunova
Keyword(s):  
Translation Regulation ◽  
Ribosomal Tunnel

Impact of microRNAs on molecular epidemiology

2011 ◽  
Vol 152 (16) ◽  
pp. 633-641 ◽  
Author(s):  
Katalin Gőcze ◽  
Katalin Gombos ◽  
Gábor Pajkos ◽  
Ingrid Magda ◽  
Ágoston Ember ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Cancer Research ◽  
Molecular Epidemiology ◽  
Wide Spectrum ◽  
Translation Regulation ◽  
Rna Sequences ◽  
Serum Mirna ◽  
The Past ◽  
Non Coding Rna ◽  
Free Serum

Cancer research concerning short non-coding RNA sequences and functionally linked to RNA interference (RNAi) have reached explosive breakthrough in the past decade. Molecular technology applies microRNA in extremely wide spectrum from molecular tumor prediction, diagnostics, progression monitoring and prevention. Functional analysis of tissue miRNA and cell-free serum miRNA in posttranscription and translation regulation innovated and restructured the knowledge on the field. This review focuses on molecular epidemiology and primary prevention aspects of the small non-coding RNA sequences. Orv. Hetil., 2011, 152, 633–641.

scholarly journals m5U54 tRNA Hypomodification by Lack of TRMT2A Drives the Generation of tRNA-Derived Small RNAs

2021 ◽  
Vol 22 (6) ◽  
pp. 2941
Author(s):  
Marisa Pereira ◽  
Diana R. Ribeiro ◽  
Miguel M. Pinheiro ◽  
Margarida Ferreira ◽  
Stefanie Kellner ◽  
...  
Keyword(s):  
Stress Response ◽  
Small Rnas ◽  
Mammalian Cells ◽  
Cellular Stress ◽  
Cellular Stress Response ◽  
Translation Regulation ◽  
Translation Efficiency ◽  
Down Regulation ◽  
Gene Expression Control ◽  
The Impact

Transfer RNA (tRNA) molecules contain various post-transcriptional modifications that are crucial for tRNA stability, translation efficiency, and fidelity. Besides their canonical roles in translation, tRNAs also originate tRNA-derived small RNAs (tsRNAs), a class of small non-coding RNAs with regulatory functions ranging from translation regulation to gene expression control and cellular stress response. Recent evidence indicates that tsRNAs are also modified, however, the impact of tRNA epitranscriptome deregulation on tsRNAs generation is only now beginning to be uncovered. The 5-methyluridine (m5U) modification at position 54 of cytosolic tRNAs is one of the most common and conserved tRNA modifications among species. The tRNA methyltransferase TRMT2A catalyzes this modification, but its biological role remains mostly unexplored. Here, we show that TRMT2A knockdown in human cells induces m5U54 tRNA hypomodification and tsRNA formation. More specifically, m5U54 hypomodification is followed by overexpression of the ribonuclease angiogenin (ANG) that cleaves tRNAs near the anticodon, resulting in accumulation of 5′tRNA-derived stress-induced RNAs (5′tiRNAs), namely 5′tiRNA-GlyGCC and 5′tiRNA-GluCTC, among others. Additionally, transcriptomic analysis confirms that down-regulation of TRMT2A and consequently m5U54 hypomodification impacts the cellular stress response and RNA stability, which is often correlated with tiRNA generation. Accordingly, exposure to oxidative stress conditions induces TRMT2A down-regulation and tiRNA formation in mammalian cells. These results establish a link between tRNA hypomethylation and ANG-dependent tsRNAs formation and unravel m5U54 as a tRNA cleavage protective mark.

Translation regulation after taxol treatment in NIH3T3 cells involves the elongation factor (eEF)2

2007 ◽  
Vol 313 (17) ◽  
pp. 3694-3706 ◽  
Author(s):  
David Piñeiro ◽  
Víctor M. González ◽  
Macarena Hernández-Jiménez ◽  
Matilde Salinas ◽  
M. Elena Martín
Keyword(s):  
Elongation Factor ◽  
Translation Regulation ◽  
Nih3t3 Cells

CBIO-23. ANTIAPOPTOTIC Bcl-xL RESTRICTS APOPTOSIS IN SHH MEDULLOBLASTOMA AND PROMOTES PROGRESSION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi31-vi32
Author(s):  
Abigail Cleveland ◽  
Katherine Veleta ◽  
Timothy Gershon
Keyword(s):  
Therapeutic Potential ◽  
Radiation Sensitivity ◽  
Genetically Engineered ◽  
Translation Regulation ◽  
Spontaneous Apoptosis ◽  
Cell Of Origin ◽  
Tumor Resistance ◽  
Cerebellar Granule Neuron ◽  
Apoptotic Pathway

Abstract Medulloblastomas in most patients are distinctively sensitive to radiation therapy, but the mechanisms that mediate this sensitivity are unclear. Current treatments still fail 20%-60% of patients with SHH medulloblastoma and can leave survivors with long-term neurocognitive and social deficits. Understanding the mechanisms driving the typical radiation-sensitivity may identify less-toxic therapeutic strategies and provide insight into treatment failure. We previously showed that radiation sensitivity depends on the intrinsic apoptotic pathway, mediated by pro-apoptotic BAX. In cerebellar granule neuron progenitors (CGNPs), the cell of origin for SHH medulloblastoma, BAX activity is directly inhibited by anti-apoptotic BCL-xL; Bcl-xL-deleted CGNPs undergo spontaneous apoptosis. To test the therapeutic potential of disrupting BCL-xL in medulloblastoma, we conditionally deleted Bcl-xL in mice genetically engineered to develop SHH medulloblastoma. Here, I show that Bcl-xL deletion slows SHH medulloblastoma growth and prolongs survival of medulloblastoma-bearing mice. Bcl-xL-deleted tumors initially showed increased rates of spontaneous apoptosis, but this effect waned over time, suggesting the emergence of BCL-xL-independent survival mechanisms. We also noted increased microglial infiltration in Bcl-xL-deleted medulloblastomas. We hypothesize that IGF1 produced by microglia in the tumor microenvironment may be contributing to tumor resistance by upregulating translation of MCL-1, an anti-apoptotic BCL-xL homolog. IGF1 is known to upregulate translation through the mTOR pathway, while anti-apoptotic MCL-1 protein abundance is dependent upon translation regulation. Our on-going studies are testing the efficacy of pharmacologically targeting BCL-xL in mice with medulloblastoma, in combination with targeting IGF1 signaling using mTORC1 inhibitors.

scholarly journals Enhanced virus translation enables miR-122-independent Hepatitis C Virus propagation

2021 ◽  
Author(s):  
Mamata Panigrahi ◽  
Michael Palmer ◽  
Joyce A Wilson
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Virus Replication ◽  
Rna Structure ◽  
Genome Stability ◽  
Internal Ribosomal Entry Site ◽  
Terminal Region ◽  
Translation Regulation ◽  
Virus Propagation ◽  
Entry Site

The 5’UTR of the Hepatitis C Virus genome forms RNA structures that regulate virus replication and translation. The region contains a viral internal ribosomal entry site and a 5’ terminal region. Binding of the liver specific miRNA, miR-122, to two conserved binding sites in the 5’ terminal region regulates viral replication, translation, and genome stability, and is essential for efficient virus replication, but its precise mechanism of its action is still under debate. A current hypothesis is that miR-122 binding stimulates viral translation by facilitating the viral 5’ UTR to form the translationally active HCV IRES RNA structure. While miR-122 is essential for detectable virus replication in cell culture, several viral variants with 5’ UTR mutations exhibit low level replication in the absence of miR-122. We show that HCV mutants capable of replicating independently of miR-122 also replicate independently of other microRNAs generated by the canonical miRNA synthesis pathway. Further, we also show that the mutant genomes display an enhanced translation phenotype that correlates with their ability to replicate independently of miR-122. Finally, we provide evidence that translation regulation is the major role for miR-122, and show that miR-122-independent HCV replication can be rescued to miR-122-dependent levels by the combined impacts of 5’ UTR mutations that stimulate translation, and by stabilizing the viral genome by knockdown of host exonucleases and phosphatases that degrade the genome. Thus, we provide a model suggesting that translation stimulation and genome stabilization are the primary roles for miR-122 in the virus life cycle.

scholarly journals Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM

2020 ◽  
Author(s):  
Anna B. Loveland ◽  
Egor Svidritskiy ◽  
Denis Susorov ◽  
Soojin Lee ◽  
Alexander Park ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Specific Binding ◽  
Structural Basis ◽  
Transferase Activity ◽  
Peptidyl Transferase ◽  
Peptidyl Transferase Center ◽  
Ribosomal Tunnel ◽  
Cellular Translation ◽  
Lateral Sclerosis ◽  
Dipeptide Repeat

AbstractToxic dipeptide repeat (DPR) proteins are produced from expanded G4C2 hexanucleotide repeats in the C9ORF72 gene, which cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two DPR proteins, poly-PR and poly-GR, repress cellular translation but the molecular mechanism remains unknown. Here we show that poly-PR and poly-GR of ≥ 20 repeats inhibit the ribosome’s peptidyl-transferase activity at nanomolar concentrations, comparable to specific translation inhibitors. High-resolution cryo-EM structures reveal that poly-PR and poly-GR block the polypeptide tunnel of the ribosome, extending into the peptidyl-transferase center. Consistent with these findings, the macrolide erythromycin, which binds in the tunnel, competes with the DPR proteins and restores peptidyl-transferase activity. Our results demonstrate that strong and specific binding of poly-PR and poly-GR in the ribosomal tunnel blocks translation, revealing the structural basis of their toxicity in C9ORF72-ALS/FTD.

scholarly journals MARK2 phosphorylates eIF2α in response to proteotoxic stress

PLoS Biology ◽  
2021 ◽  
Vol 19 (3) ◽  
pp. e3001096
Author(s):  
Yu-Ning Lu ◽  
Sarah Kavianpour ◽  
Tao Zhang ◽  
Xumei Zhang ◽  
Dao Nguyen ◽  
...  
Keyword(s):  
Stress Responses ◽  
Protein Misfolding ◽  
Critical Role ◽  
Heat Shock Protein 90 ◽  
Human Diseases ◽  
Initiation Factor ◽  
Translation Regulation ◽  
Proteotoxic Stress ◽  
Initiation Factor 2 ◽  
Lateral Sclerosis

The regulation of protein synthesis is essential for maintaining cellular homeostasis, especially during stress responses, and its dysregulation could underlie the development of human diseases. The critical step during translation regulation is the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α). Here we report the identification of a direct kinase of eIF2α, microtubule affinity-regulating kinase 2 (MARK2), which phosphorylates eIF2α in response to proteotoxic stress. The activity of MARK2 was confirmed in the cells lacking the 4 previously known eIF2α kinases. MARK2 itself was found to be a substrate of protein kinase C delta (PKCδ), which serves as a sensor for protein misfolding stress through a dynamic interaction with heat shock protein 90 (HSP90). Both MARK2 and PKCδ are activated via phosphorylation in proteotoxicity-associated neurodegenerative mouse models and in human patients with amyotrophic lateral sclerosis (ALS). These results reveal a PKCδ-MARK2-eIF2α cascade that may play a critical role in cellular proteotoxic stress responses and human diseases.

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