scholarly journals UPF1/SMG7-dependent microRNA-mediated gene regulation

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Jungyun Park ◽  
Jwa-Won Seo ◽  
Narae Ahn ◽  
Seokju Park ◽  
Jungwook Hwang ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Regulatory Network ◽  
Mrna Decay ◽  
Complex Interaction ◽  
Dependent Manner ◽  
Detailed Mechanism ◽  
Nonsense Mediated Mrna Decay ◽  
The Stability ◽  
Mirna Targeting

Abstract The stability and quality of metazoan mRNAs are under microRNA (miRNA)-mediated and nonsense-mediated control. Although UPF1, a core mediator of nonsense-mediated mRNA decay (NMD), mediates the decay of target mRNA in a 3′UTR-length-dependent manner, the detailed mechanism remains unclear. Here, we suggest that 3′UTR-length-dependent mRNA decay is not mediated by nonsense mRNAs but rather by miRNAs that downregulate target mRNAs via Ago-associated UPF1/SMG7. Global analyses of mRNAs in response to UPF1 RNA interference in miRNA-deficient cells reveal that 3′UTR-length-dependent mRNA decay by UPF1 requires canonical miRNA targeting. The destabilization of miRNA targets is accomplished by the combination of Ago2 and UPF1/SMG7, which may recruit the CCR4-NOT deadenylase complex. Indeed, loss of the SMG7-deadenylase complex interaction increases the levels of transcripts regulated by UPF1-SMG7. This UPF1/SMG7-dependent miRNA-mediated mRNA decay pathway may enable miRNA targeting to become more predictable and expand the miRNA-mRNA regulatory network.

scholarly journals SMG-1 Is a Phosphatidylinositol Kinase-Related Protein Kinase Required for Nonsense-Mediated mRNA Decay in Caenorhabditis elegans

2004 ◽  
Vol 24 (17) ◽  
pp. 7483-7490 ◽  
Author(s):  
Andrew Grimson ◽  
Sean O'Connor ◽  
Carrie Loushin Newman ◽  
Philip Anderson
Keyword(s):  
Protein Kinase ◽  
Mammalian Cells ◽  
Mrna Decay ◽  
Null Alleles ◽  
Dependent Manner ◽  
Messenger Rnas ◽  
Phosphatidylinositol Kinase ◽  
Nonsense Mediated Mrna Decay

ABSTRACT Eukaryotic messenger RNAs containing premature stop codons are selectively and rapidly degraded, a phenomenon termed nonsense-mediated mRNA decay (NMD). Previous studies with both Caenohabditis elegans and mammalian cells indicate that SMG-2/human UPF1, a central regulator of NMD, is phosphorylated in an SMG-1-dependent manner. We report here that smg-1, which is required for NMD in C. elegans, encodes a protein kinase of the phosphatidylinositol kinase superfamily of protein kinases. We identify null alleles of smg-1 and demonstrate that SMG-1 kinase activity is required in vivo for NMD and in vitro for SMG-2 phosphorylation. SMG-1 and SMG-2 coimmunoprecipitate from crude extracts, and this interaction is maintained in smg-3 and smg-4 mutants, both of which are required for SMG-2 phosphorylation in vivo and in vitro. SMG-2 is located diffusely through the cytoplasm, and its location is unaltered in mutants that disrupt the cycle of SMG-2 phosphorylation. We discuss the role of SMG-2 phosphorylation in NMD.

scholarly journals Smg5 is required for multiple nonsense-mediated mRNA decay pathways in Drosophila

2017 ◽  
Author(s):  
Jonathan O. Nelson ◽  
Dominique Förster ◽  
Kimberly A. Frizzell ◽  
Stefan Luschnig ◽  
Mark M. Metzstein
Keyword(s):  
Mrna Decay ◽  
The Other ◽  
Dependent Manner ◽  
Partial Loss ◽  
Endonucleolytic Cleavage ◽  
Nonsense Mediated Mrna Decay ◽  
Gene Regulatory ◽  
The Individual ◽  
Multicellular Organisms

ABSTRACTThe nonsense-mediated mRNA decay (NMD) pathway is a cellular quality control and post-transcriptional gene regulatory mechanism and is essential for viability in most multicellular organisms. A complex of proteins has been identified to be required for NMD function to occur, however the individual contribution of each of these factors to the NMD process is not well understood. Central to the NMD process are two proteins Upf1 (SMG-2) and Upf2 (SMG-3), which are found in all eukaryotes and are absolutely required for NMD in all organisms in which it has been examined. The other known NMD factors, Smg1, Smg5, Smg6, and Smg7 are more variable in their presence in different orders of organisms, and are thought to have a more regulatory role. Here we present the first genetic analysis of the NMD factor Smg5 in Drosophila. Surprisingly, we find that unlike the other analyzed Smg genes in this organism, Smg5 is essential for NMD activity. We found this is due at least in part to a role for Smg5 in the activity of two separable NMD-target decay mechanisms: endonucleolytic cleavage and 5′-to-3′ exonucleolytic decay. Redundancy between these degradation pathways explains why some Drosophila NMD genes are not required for all NMD-pathway activity. We also found that while the NMD component Smg1 has only a minimal role in Drosophila NMD during normal conditions, it becomes essential when NMD activity is compromised by partial loss of Smg5 function. Our findings suggest that not all NMD complex components are required for NMD function at all times, but instead are utilized in a context dependent manner in vivo.

Plant upstream ORFs can trigger nonsense-mediated mRNA decay in a size-dependent manner

2009 ◽  
Vol 71 (4-5) ◽  
pp. 367-378 ◽  
Author(s):  
Tünde Nyikó ◽  
Boglárka Sonkoly ◽  
Zsuzsanna Mérai ◽  
Anna Hangyáné Benkovics ◽  
Dániel Silhavy
Keyword(s):  
Mrna Decay ◽  
Dependent Manner ◽  
Size Dependent ◽  
Nonsense Mediated Mrna Decay

scholarly journals Role of AT1G72910, AT1G72940, and ADR1-LIKE 2 in Plant Immunity under Nonsense-Mediated mRNA Decay-Compromised Conditions at Low Temperatures

2020 ◽  
Vol 21 (21) ◽  
pp. 7986
Author(s):  
Zeeshan Nasim ◽  
Muhammad Fahim ◽  
Katarzyna Gawarecka ◽  
Hendry Susila ◽  
Suhyun Jin ◽  
...  
Keyword(s):  
Pseudomonas Syringae ◽  
Mrna Decay ◽  
Degradation Kinetics ◽  
Plant Immunity ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Temperature Dependent ◽  
Stunted Growth ◽  
Nonsense Mediated Mrna Decay

Nonsense-mediated mRNA decay (NMD) removes aberrant transcripts to avoid the accumulation of truncated proteins. NMD regulates nucleotide-binding, leucine-rich repeat (NLR) genes to prevent autoimmunity; however, the function of a large number of NLRs still remains poorly understood. Here, we show that three NLR genes (AT1G72910, AT1G72940, and ADR1-LIKE 2) are important for NMD-mediated regulation of defense signaling at lower temperatures. At 16 °C, the NMD-compromised up-frameshift protein1 (upf1) upf3 mutants showed growth arrest that can be rescued by the artificial miRNA-mediated knockdown of the three NLR genes. mRNA levels of these NLRs are induced by Pseudomonas syringae inoculation and exogenous SA treatment. Mutations in AT1G72910, AT1G72940, and ADR1-LIKE 2 genes resulted in increased susceptibility to Pseudomonas syringae, whereas their overexpression resulted in severely stunted growth, which was dependent on basal disease resistance genes. The NMD-deficient upf1 upf3 mutants accumulated higher levels of NMD signature-containing transcripts from these NLR genes at 16 °C. Furthermore, mRNA degradation kinetics showed that these NMD signature-containing transcripts were more stable in upf1 upf3 mutants. Based on these findings, we propose that AT1G72910, AT1G72940, and ADR1-LIKE 2 are directly regulated by NMD in a temperature-dependent manner and play an important role in modulating plant immunity at lower temperatures.

scholarly journals Networks of Splice Factor Regulation by Unproductive Splicing Coupled With Nonsense Mediated mRNA Decay

2020 ◽  
Author(s):  
Anna Desai ◽  
Zhiqiang Hu ◽  
Courtney E. French ◽  
James P. B. Lloyd ◽  
Steven E. Brenner
Keyword(s):  
Transcription Factors ◽  
Alternative Splicing ◽  
Regulatory Network ◽  
Mrna Decay ◽  
Current Knowledge ◽  
Interaction Network ◽  
Splicing Factor ◽  
Splicing Factors ◽  
Extensive Literature ◽  
Nonsense Mediated Mrna Decay

AbstractBackgroundNonsense mediated mRNA decay (NMD) is an RNA surveillance pathway that degrades aberrant transcripts harboring premature termination codons. This pathway, in conjunction with alternative splicing, regulates gene expression post-transcriptionally. Nearly all serine and arginine-rich (SR) proteins and many heterogeneous nuclear ribonucleoproteins (hnRNPs) produce isoforms that can be degraded by the NMD pathway. Many splicing factors have been reported to be regulated via alternative splicing coupled to NMD. However, it is still uncharacterized that to what extent NMD contributes to the regulation of splicing factors.ResultsHere, we characterized a regulatory network of splicing factors through alternative splicing coupled to NMD. Based upon an extensive literature search, we first assembled a network that encompasses the current knowledge of splice factors repressing or activating the expression of other splicing factors through alternative splicing coupled to NMD. This regulatory network is limited, including just a handful of well-studied splicing factors. To gain a more global and less biased overview, we examined the splicing factor-mRNA interactions from public crosslinking-immunoprecipitation (CLIP)-seq data, which provides information about protein–RNA interactions. A network view of these interactions reveals extensive binding among splicing regulators. We also found that splicing factors bind more frequently to transcripts of other splicing factors than to other genes. In addition, many splicing factors are targets of NMD, and might be regulated via alternative splicing coupled to NMD, which is demonstrated by the significant overlap between the experimental network and eCLIP-network. We found that hierarchy of the splicing-factor interaction network differs from the hierarchy observed for transcription factors.ConclusionThe extensive interaction between splicing factors and transcripts of other splicing factors suggests that the potential regulation via alternative splicing coupled with NMD is widespread. The splicing factor regulation is fundamentally different from that of transcription factors.

Nonsense-Mediated mRNA Decay Deficiency Affects the Auxin Response and Shoot Regeneration in Arabidopsis

2019 ◽  
Vol 60 (9) ◽  
pp. 2000-2014 ◽  
Author(s):  
Nyet-Cheng Chiam ◽  
Tomoyo Fujimura ◽  
Ryosuke Sano ◽  
Nobuhiro Akiyoshi ◽  
Ryoko Hiroyama ◽  
...  
Keyword(s):  
Shoot Regeneration ◽  
Mrna Decay ◽  
Callus Formation ◽  
Expression Patterns ◽  
Adventitious Shoots ◽  
Induction Medium ◽  
Dependent Manner ◽  
Auxin Response ◽  
Nonsense Mediated Mrna Decay ◽  
Shoot Induction Medium

Abstract Plants generally possess a strong ability to regenerate organs; for example, in tissue culture, shoots can regenerate from callus, a clump of actively proliferating, undifferentiated cells. Processing of pre-mRNA and ribosomal RNAs is important for callus formation and shoot regeneration. However, our knowledge of the roles of RNA quality control via the nonsense-mediated mRNA decay (NMD) pathway in shoot regeneration is limited. Here, we examined the shoot regeneration phenotypes of the low-beta-amylase1 (lba1)/upstream frame shift1-1 (upf1-1) and upf3-1 mutants, in which the core NMD components UPF1 and UPF3 are defective. These mutants formed callus from hypocotyl explants normally, but this callus behaved abnormally during shoot regeneration: the mutant callus generated numerous adventitious root structures instead of adventitious shoots in an auxin-dependent manner. Quantitative RT-PCR and microarray analyses showed that the upf mutations had widespread effects during culture on shoot-induction medium. In particular, the expression patterns of early auxin response genes, including those encoding AUXIN/INDOLE ACETIC ACID (AUX/IAA) family members, were significantly affected in the upf mutants. Also, the upregulation of shoot apical meristem-related transcription factor genes, such as CUP-SHAPED COTYLEDON1 (CUC1) and CUC2, was inhibited in the mutants. Taken together, these results indicate that NMD-mediated transcriptomic regulation modulates the auxin response in plants and thus plays crucial roles in the early stages of shoot regeneration.

scholarly journals Deciphering the nonsense-mediated mRNA decay pathway to identify cancer cell vulnerabilities for effective cancer therapy

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Roberta Bongiorno ◽  
Mario Paolo Colombo ◽  
Daniele Lecis
Keyword(s):  
Tumor Suppressor ◽  
Cancer Cell ◽  
Mrna Decay ◽  
Genetic Diseases ◽  
Cell Physiology ◽  
Therapeutic Opportunity ◽  
Nonsense Mediated Mrna Decay ◽  
Regulation Mechanisms ◽  
The Stability ◽  
Surveillance Mechanism

AbstractNonsense-mediated mRNA decay (NMD) is a highly conserved cellular surveillance mechanism, commonly studied for its role in mRNA quality control because of its capacity of degrading mutated mRNAs that would produce truncated proteins. However, recent studies have proven that NMD hides more complex tasks involved in a plethora of cellular activities. Indeed, it can control the stability of mutated as well as non-mutated transcripts, tuning transcriptome regulation. NMD not only displays a pivotal role in cell physiology but also in a number of genetic diseases. In cancer, the activity of this pathway is extremely complex and it is endowed with both pro-tumor and tumor suppressor functions, likely depending on the genetic context and tumor microenvironment. NMD inhibition has been tested in pre-clinical studies showing favored production of neoantigens by cancer cells, which can stimulate the triggering of an anti-tumor immune response. At the same time, NMD inhibition could result in a pro-tumor effect, increasing cancer cell adaptation to stress. Since several NMD inhibitors are already available in the clinic to treat genetic diseases, these compounds could be redirected to treat cancer patients, pending the comprehension of these variegated NMD regulation mechanisms. Ideally, an effective strategy should exploit the anti-tumor advantages of NMD inhibition and simultaneously preserve its intrinsic tumor suppressor functions. The targeting of NMD could provide a new therapeutic opportunity, increasing the immunogenicity of tumors and potentially boosting the efficacy of the immunotherapy agents now available for cancer treatment.

Criteria for evaluation of the coordinate measurements quality of parts geometric parameters at pilot-experimental production

2019 ◽  
pp. 3-8
Author(s):  
N.Yu. Bobrovskaya ◽  
M.F. Danilov
Keyword(s):  
Quality Indicators ◽  
Quality Management System ◽  
Technical Specification ◽  
Experimental Production ◽  
Technological Heredity ◽  
Coordinate Measurements ◽  
Reasonable Choice ◽  
The Stability ◽  
Geometric Elements

The criteria of the coordinate measurements quality at pilot-experimental production based on contemporary methods of quality management system and traditional methods of the measurements quality in Metrology are considered. As an additional criterion for quality of measurements, their duration is proposed. Analyzing the problem of assessing the quality of measurements, the authors pay particular attention to the role of technological heredity in the analysis of the sources of uncertainty of coordinate measurements, including not only the process of manufacturing the part, but all stages of the development of design and technological documentation. Along with such criteria as the degree of confidence in the results of measurements; the accuracy, convergence, reproducibility and speed of the results must take into account the correctness of technical specification, and such characteristics of the shape of the geometric elements to be controlled, such as flatness, roundness, cylindrical. It is noted that one of the main methods to reduce the uncertainty of coordinate measurements is to reduce the uncertainty in the initial data and measurement conditions, as well as to increase the stability of the tasks due to the reasonable choice of the basic geometric elements (measuring bases) of the part. A prerequisite for obtaining reliable quality indicators is a quantitative assessment of the conditions and organization of the measurement process. To plan and normalize the time of measurements, the authors propose to use analytical formulas, on the basis of which it is possible to perform quantitative analysis and optimization of quality indicators, including the speed of measurements.

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