scholarly journals Progressive polysomal association of Upf1, Upf2, and Upf3 as ribosomes traverse mRNA coding regions

2021 ◽  
Author(s):  
Robin Ganesan ◽  
Kotchaphorn Mangkalaphiban ◽  
Richard E. Baker ◽  
Feng He ◽  
Allan Jacobson
Keyword(s):  
Mrna Translation ◽  
Premature Termination Codon ◽  
Ribosome Profiling ◽  
Yeast Genetics ◽  
Wild Type ◽  
Ribosome Binding ◽  
Coding Regions ◽  
Mrna Surveillance ◽  
Nonsense Mediated Mrna Decay

SUMMARYUpf1, Upf2, and Upf3 are the central regulators of nonsense-mediated mRNA decay (NMD), the eukaryotic mRNA quality control pathway generally triggered when a premature termination codon is recognized by the ribosome. The NMD-related functions of the Upf proteins likely commence while these factors are ribosome-associated, but little is known of the timing of their ribosome binding, their specificity for ribosomes translating NMD substrates, or the nature and role of any ribosome:Upf complexes. Here, we have elucidated details of the ribosome-associated steps of NMD. By combining yeast genetics with selective ribosome profiling and co-sedimentation analyses of polysomes with wild-type and mutant Upf proteins, our approaches have identified distinct states of ribosome:Upf association. All three Upf factors manifest progressive polysome association as mRNA translation proceeds, but these events appear to be preceded by formation of a Upf1:80S complex as mRNAs initiate translation. This complex is likely executing an early mRNA surveillance function.

scholarly journals LQT2 nonsense mutations generate trafficking defective NH2-terminally truncated channels by the reinitiation of translation

2013 ◽  
Vol 305 (9) ◽  
pp. H1397-H1404 ◽  
Author(s):  
Matthew R. Stump ◽  
Qiuming Gong ◽  
Zhengfeng Zhou
Keyword(s):  
Ventricular Arrhythmias ◽  
Premature Termination Codon ◽  
Wild Type ◽  
Autosomal Dominant Disorder ◽  
Nonsense Mutations ◽  
Accelerated Degradation ◽  
Herg Current ◽  
Nonsense Mediated Mrna Decay ◽  
Herg Channels

The human ether-a-go-go-related gene ( hERG) encodes a voltage-activated K+ channel that contributes to the repolarization of the cardiac action potential. Long QT syndrome type 2 (LQT2) is an autosomal dominant disorder caused by mutations in hERG, and patients with LQT2 are susceptible to severe ventricular arrhythmias. We have previously shown that nonsense and frameshift LQT2 mutations caused a decrease in mutant mRNA by the nonsense-mediated mRNA decay (NMD) pathway. The Q81X nonsense mutation was recently found to be resistant to NMD. Translation of Q81X is reinitiated at Met124, resulting in the generation of NH2-terminally truncated hERG channels with altered gating properties. In the present study, we identified two additional NMD-resistant LQT2 nonsense mutations, C39X and C44X, in which translation is reinitiated at Met60. Deletion of the first 59 residues of the channel truncated nearly one-third of the highly structured Per-Arnt-Sim domain and resulted in the generation of trafficking-defective proteins and a complete loss of hERG current. Partial deletion of the Per-Arnt-Sim domain also resulted in the accelerated degradation of the mutant channel proteins. The coexpression of mutant and wild-type channels did not significantly disrupt the function and trafficking properties of wild-type hERG. Our present findings indicate that translation reinitiation may generate trafficking-defective as well as dysfunctional channels in patients with LQT2 premature termination codon mutations that occur early in the coding sequence.

scholarly journals CLK-2/TEL2 is a conserved component of the nonsense-mediated mRNA decay pathway

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0244505
Author(s):  
Yanwu Guo ◽  
Cristina Tocchini ◽  
Rafal Ciosk
Keyword(s):  
Mrna Decay ◽  
Forward Genetics ◽  
Morphological Effect ◽  
Dna Damage Signaling ◽  
Mrna Surveillance ◽  
Genetic Landscape ◽  
Nonsense Mediated Mrna Decay ◽  
Novel Strategy ◽  
Conserved Gene

Nonsense-mediated mRNA decay (NMD) controls eukaryotic mRNA quality, inducing the degradation of faulty transcripts. Key players in the NMD pathway were originally identified, through genetics, in Caenorhabditis elegans as smg (suppressor with morphological effect on genitalia) genes. Using forward genetics and fluorescence-based NMD reporters, we reexamined the genetic landscape underlying NMD. Employing a novel strategy for mapping sterile mutations, Het-Map, we identified clk-2, a conserved gene previously implicated in DNA damage signaling, as a player in the nematode NMD. We find that CLK-2 is expressed predominantly in the germline, highlighting the importance of auxiliary factors in tissue-specific mRNA decay. Importantly, the human counterpart of CLK-2/TEL2, TELO2, has been also implicated in the NMD, suggesting a conserved role of CLK-2/TEL2 proteins in mRNA surveillance. Recently, variants of TELO2 have been linked to an intellectual disability disorder, the You-Hoover-Fong syndrome, which could be related to its function in the NMD.

scholarly journals Slowed decay of mRNAs enhances platelet specific translation

Blood ◽  
2017 ◽  
Vol 129 (17) ◽  
pp. e38-e48 ◽  
Author(s):  
Eric W. Mills ◽  
Rachel Green ◽  
Nicholas T. Ingolia
Keyword(s):  
Human Platelets ◽  
Ribosome Profiling ◽  
Rna Decay ◽  
Wild Type ◽  
Key Points ◽  
Mrna Surveillance

Key Points Ribosome profiling of primary human platelets defines the platelet translatome, derived from a biased subset of MK mRNAs. Restoration of the ribosome rescue/mRNA surveillance factor Pelota, which is normally absent in wild-type platelets, promotes RNA decay.

The nuclear cap-binding protein complex is not essential for nonsense-mediated mRNA decay (NMD) in plants.

2008 ◽  
Vol 55 (4) ◽  
pp. 825-828 ◽  
Author(s):  
Agnieszka Dzikiewicz-Krawczyk ◽  
Paulina Piontek ◽  
Zofia Szweykowska-Kulińska ◽  
Artur Jarmołowski
Keyword(s):  
Protein Complex ◽  
Mrna Decay ◽  
Splice Variants ◽  
Binding Protein ◽  
Direct Sequencing ◽  
Premature Termination Codon ◽  
Wild Type ◽  
Mrna Variants ◽  
Nonsense Mediated Mrna Decay ◽  
Alternatively Spliced

In this study we investigated whether in plants, like in mammals, components of the nuclear cap-binding protein complex (CBC) are involved in nonsense-mediated mRNA decay (NMD). We selected several genes producing at least two alternatively spliced mRNA variants: one with a premature termination codon (PTC+) and another without it (PTC-). For each gene the PTC+/PTC- ratio was calculated using RT-PCR and direct sequencing in four Arabidopsis thaliana lines: wild type, the NMD mutant atupf3-1 and two CBC mutants: cbp20 and abh1. Whereas in the NMD mutant the ratios of PTC+/PTC- splice variants were higher than in wild-type plants, the two CBC mutants investigated showed no change in the PTC+/PTC- ratios. Our results suggest that neither CBP20 nor CBP80 is involved in NMD in A. thaliana.

scholarly journals Regulation of nonsense-mediated mRNA decay in neural development and disease

2021 ◽  
Author(s):  
Paul Jongseo Lee ◽  
Suzhou Yang ◽  
Yu Sun ◽  
Junjie U Guo
Keyword(s):  
Neural Development ◽  
Mrna Decay ◽  
Developmental Regulation ◽  
Critical Role ◽  
Premature Termination Codon ◽  
Regulation Mechanism ◽  
Genes Encoding ◽  
Nonsense Mediated Mrna Decay ◽  
Quality Control Mechanism

Abstract Eukaryotes have evolved a variety of mRNA surveillance mechanisms to detect and degrade aberrant mRNAs with potential deleterious outcomes. Among them, nonsense-mediated mRNA decay (NMD) functions not only as a quality control mechanism targeting aberrant mRNAs containing a premature termination codon (PTC), but also as a post-transcriptional gene regulation mechanism targeting numerous physiological mRNAs. Despite its well-characterized molecular basis, the regulatory scope and biological functions of NMD at an organismal level are incompletely understood. In humans, mutations in genes encoding core NMD factors cause specific developmental and neurological syndromes, suggesting a critical role of NMD in the central nervous system. Here, we review the accumulating biochemical and genetic evidence on the developmental regulation and physiological functions of NMD, as well as an emerging role of NMD dysregulation in neurodegenerative diseases.

Differential Role of Components of the Fibrinolytic System in the Formation and Removal of Thrombus Induced by Endothelial Injury

1999 ◽  
Vol 81 (04) ◽  
pp. 601-604 ◽  
Author(s):  
Hiroyuki Matsuno ◽  
Osamu Kozawa ◽  
Masayuki Niwa ◽  
Shigeru Ueshima ◽  
Osamu Matsuo ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Thrombus Formation ◽  
Endothelial Injury ◽  
Fibrinolytic System ◽  
Tissue Type ◽  
Clot Lysis ◽  
Wild Type ◽  
Type Plasminogen Activator ◽  
Pai 1

SummaryThe role of fibrinolytic system components in thrombus formation and removal in vivo was investigated in groups of six mice deficient in urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA), or plasminogen activator inhibitor-1 (PAI-1) (u-PA-/-, t-PA-/- or PAI-1-/-, respectively) or of their wild type controls (u-PA+/+, t-PA+/+ or PAI-1+/+). Thrombus was induced in the murine carotid artery by endothelial injury using the photochemical reaction between rose bengal and green light (540 nm). Blood flow was continuously monitored for 90 min on day 0 and for 20 min on days 1, 2 and 3. The times to occlusion after the initiation of endothelial injury in u-PA+/+, t-PA+/+ or PAI-1+/+ mice were 9.4 ± 1.3, 9.8 ± 1.1 or 9.7 ± 1.6 min, respectively. u-PA-/- and t-PA-/- mice were indistinguishable from controls, whereas that of PAI-1-/- mice were significantly prolonged (18.4 ± 3.7 min). Occlusion persisted for the initial 90 min observation period in 10 of 18 wild type mice and was followed by cyclic reflow and reocclusion in the remaining 8 mice. At day 1, persistent occlusion was observed in 1 wild type mouse, 8 mice had cyclic reflow and reocclusion and 9 mice had persistent reflow. At day 2, all injured arteries had persistent reflow. Persistent occlusion for 90 min on day 0 was observed in 3 u-PA-/-, in all t-PA-/- mice at day 1 and in 2 of the t-PA-/-mice at day 2 (p <0.01 versus wild type mice). Persistent patency was observed in all PAI-1-/- mice at day 1 and in 5 of the 6 u-PA-/- mice at day 2 (both p <0.05 versus wild type mice). In conclusion, t-PA increases the rate of clot lysis after endothelial injury, PAI-1 reduces the time to occlusion and delays clot lysis, whereas u-PA has little effect on thrombus formation and spontaneous lysis.

Sign in / Sign up

Export Citation Format

Share Document