UPF1 involvement in nuclear functions

2012 ◽  
Vol 40 (4) ◽  
pp. 778-783 ◽  
Author(s):  
Wazeer Varsally ◽  
Saverio Brogna
Keyword(s):  
Dna Replication ◽  
Cell Cycle Progression ◽  
Translation Termination ◽  
Interaction Network ◽  
Rna Degradation ◽  
Telomere Maintenance ◽  
Human Proteins ◽  
Nonsense Mediated Mrna Decay ◽  
Rapid Destruction ◽  
Translation Termination Codon

UPF1 (up-frameshift 1) is a protein conserved in all eukaryotes that is necessary for NMD (nonsense-mediated mRNA decay). UPF1 mainly localizes to the cytoplasm and, via mechanisms that are linked to translation termination but not yet well understood, stimulates rapid destruction of mRNAs carrying a PTC (premature translation termination codon). However, some studies have indicated that in human cells UPF1 has additional roles, possibly unrelated to NMD, which are carried out in the nucleus. These might involve telomere maintenance, cell cycle progression and DNA replication. In the present paper, we review the available experimental evidence implicating UPF1 in nuclear functions. The unexpected view that emerges from this literature is that the nuclear functions primarily stem from UPF1 having an important role in DNA replication, rather than NMD affecting the expression of proteins involved in these processes. Our bioinformatics survey of the interaction network of UPF1 with other human proteins, however, highlights that UPF1 also interacts with proteins associated with nuclear RNA degradation and transcription termination; therefore suggesting involvement in processes that could also impinge on DNA replication indirectly.

scholarly journals Detection and Degradation of Nonsense-mediated mRNA Decay Substrates Involve Two Distinct Upf1-bound Complexes

2018 ◽  
Author(s):  
Marine Dehecq ◽  
Laurence Decourty ◽  
Abdelkader Namane ◽  
Caroline Proux ◽  
Joanne Kanaan ◽  
...  
Keyword(s):  
Large Scale ◽  
Mrna Decay ◽  
Affinity Purification ◽  
Rna Degradation ◽  
Degradation Pathway ◽  
Telomere Maintenance ◽  
Mrna Decapping ◽  
Nonsense Mediated Mrna Decay ◽  
Decapping Enzyme

AbstractNonsense-mediated mRNA decay (NMD) is a translation-dependent RNA degradation pathway involved in many cellular pathways and crucial for telomere maintenance and embryo development. Core NMD factors Upf1, Upf2 and Upf3 are conserved from yeast to mammals, but a universal NMD model is lacking. We used affinity purification coupled with mass spectrometry and an improved data analysis protocol to obtain the first large-scale quantitative characterization of yeast NMD complexes in yeast (112 experiments). Unexpectedly, we identified two distinct complexes associated with Upf1: Detector (Upf1/2/3) and Effector. Effector contained the mRNA decapping enzyme, together with Nmd4 and Ebs1, two proteins that globally affected NMD and were critical for RNA degradation mediated by the Upf1 C-terminal helicase region. The fact that Nmd4 association to RNA was dependent on Detector components and the similarity between Nmd4/Ebs1 and mammalian Smg5-7 proteins suggest that in all eukaryotes NMD operates through successive Upf1-bound Detector and Effector complexes.

scholarly journals A role for DIS3L2 over human nonsense-mediated mRNA decay targets

2019 ◽  
Author(s):  
Paulo J. da Costa ◽  
Juliane Menezes ◽  
Margarida Saramago ◽  
Juan F. García-Moreno ◽  
Hugo A. Santos ◽  
...  
Keyword(s):  
Translation Termination ◽  
Full Length ◽  
Nonsense Mediated Decay ◽  
Endonucleolytic Cleavage ◽  
Nonsense Mediated Mrna Decay ◽  
Translation Termination Codon ◽  
Life Analysis ◽  
Mrna Half Life ◽  
Premature Translation Termination Codon

ABSTRACTThe nonsense-mediated decay (NMD) pathway selectively degrades mRNAs carrying a premature translation-termination codon but also regulates the abundance of a large number of physiological mRNAs that encode full-length proteins. In human cells, NMD-targeted mRNAs are degraded by endonucleolytic cleavage and exonucleolytic degradation from both 5’ and 3’ ends. This is done by a process not yet completely understood that recruits decapping and 5’-to-3’ exonuclease activities, as well as deadenylating and 3’-to-5’ exonuclease exosome activities. In yeast, DIS3/Rrp44 protein is the catalytic subunit of the exosome, but in humans, there are three known paralogues of this enzyme: DIS3, DIS3L1, and DIS3L2. DIS3L1 and DIS3L2 exoribonucleases localize in the same compartment where NMD occurs, but little is known about their role in this process. In order to unveil the role of DIS3L2 in NMD, here we show that some NMD-targets accumulate in DIS3L2-depleted cells. mRNA half-life analysis further supports that these NMD-targets are in fact DIS3L2 substrates. Besides, we observed that DIS3L2 acts over full-length transcripts, through a process that also involves UPF1. Moreover, DIS3L2-mediated decay is dependent on the activity of the terminal uridylyl transferases Zcchc6/11 (TUT7/4). Together, our findings establish a role for DIS3L2 and uridylation in NMD.

scholarly journals An intron proximal to a PTC enhances NMD in Saccharomyces cerevisiae

2017 ◽  
Author(s):  
Jikai Wen ◽  
Muyang He ◽  
Marija Petric ◽  
Laetitia Marzi ◽  
Jianming Wang ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Mammalian Cells ◽  
Mrna Decay ◽  
Translation Termination ◽  
Exon Junction Complex ◽  
Coding Region ◽  
Independent Mechanism ◽  
Nonsense Mediated Mrna Decay ◽  
Translation Termination Codon ◽  
Premature Translation Termination Codon

AbstractNonsense mediated mRNA decay (NMD) is regarded as the function of a specialized cytoplasmic translation-coupled mRNA decay pathway in eukaryotes, however, whether a premature translation termination codon (PTC) will lead to NMD often depends on splicing a downstream intron in the nucleus. Deposition of the exon junction complex (EJC) on mRNA is understood to mediate such splicing-dependent NMD in mammalian cells. The budding yeast, Saccharomyces cerevisiae, which has introns in only 5% of its genes, characteristically at the start of the coding region, and lacks proteins essential for EJC assembly, is not expected to undergo splicing-dependent NMD. However, we found that the presence of an intron near a PTC can also enhance NMD in this organism, regardless of whether it is downstream or upstream. These data provide evidence for a hitherto unsuspected EJC-independent mechanism linking translation and pre-mRNA in S. cerevisiae.

scholarly journals Improving the Understanding of Pathogenesis of Human Papillomavirus 16 via Mapping Protein-Protein Interaction Network

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Yongcheng Dong ◽  
Qifan Kuang ◽  
Xu Dai ◽  
Rong Li ◽  
Yiming Wu ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Protein Interaction ◽  
Cell Cycle Progression ◽  
Interaction Network ◽  
Support Vector ◽  
Human Papillomavirus 16 ◽  
Protein Protein Interaction ◽  
Topological Features ◽  
Broad Array ◽  
Human Proteins

The human papillomavirus 16 (HPV16) has high risk to lead various cancers and afflictions, especially, the cervical cancer. Therefore, investigating the pathogenesis of HPV16 is very important for public health. Protein-protein interaction (PPI) network between HPV16 and human was used as a measure to improve our understanding of its pathogenesis. By adopting sequence and topological features, a support vector machine (SVM) model was built to predict new interactions between HPV16 and human proteins. All interactions were comprehensively investigated and analyzed. The analysis indicated that HPV16 enlarged its scope of influence by interacting with human proteins as much as possible. These interactions alter a broad array of cell cycle progression. Furthermore, not only was HPV16 highly prone to interact with hub proteins and bottleneck proteins, but also it could effectively affect a breadth of signaling pathways. In addition, we found that the HPV16 evolved into high carcinogenicity on the condition that its own reproduction had been ensured. Meanwhile, this work will contribute to providing potential new targets for antiviral therapeutics and help experimental research in the future.

scholarly journals Regulation of Cell Division in Bacteria by Monitoring Genome Integrity and DNA Replication Status

2019 ◽  
Vol 202 (2) ◽  
Author(s):  
Peter E. Burby ◽  
Lyle A. Simmons
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Division ◽  
Dna Replication ◽  
Cell Cycle Progression ◽  
Genome Instability ◽  
Sos Response ◽  
Bacterial Cells ◽  
Cycle Progression ◽  
Content Type

ABSTRACT All organisms regulate cell cycle progression by coordinating cell division with DNA replication status. In eukaryotes, DNA damage or problems with replication fork progression induce the DNA damage response (DDR), causing cyclin-dependent kinases to remain active, preventing further cell cycle progression until replication and repair are complete. In bacteria, cell division is coordinated with chromosome segregation, preventing cell division ring formation over the nucleoid in a process termed nucleoid occlusion. In addition to nucleoid occlusion, bacteria induce the SOS response after replication forks encounter DNA damage or impediments that slow or block their progression. During SOS induction, Escherichia coli expresses a cytoplasmic protein, SulA, that inhibits cell division by directly binding FtsZ. After the SOS response is turned off, SulA is degraded by Lon protease, allowing for cell division to resume. Recently, it has become clear that SulA is restricted to bacteria closely related to E. coli and that most bacteria enforce the DNA damage checkpoint by expressing a small integral membrane protein. Resumption of cell division is then mediated by membrane-bound proteases that cleave the cell division inhibitor. Further, many bacterial cells have mechanisms to inhibit cell division that are regulated independently from the canonical LexA-mediated SOS response. In this review, we discuss several pathways used by bacteria to prevent cell division from occurring when genome instability is detected or before the chromosome has been fully replicated and segregated.

scholarly journals Whole-genome sequencing of recurrent neuroblastoma reveals somatic mutations that affect key players in cancer progression and telomere maintenance

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Susanne Fransson ◽  
Angela Martinez-Monleon ◽  
Mathias Johansson ◽  
Rose-Marie Sjöberg ◽  
Caroline Björklund ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Cancer Progression ◽  
Cell Cycle Progression ◽  
Mapk Signaling ◽  
Telomere Maintenance ◽  
Whole Genome ◽  
Genomic Alterations ◽  
Cycle Progression

AbstractNeuroblastoma is the most common and deadly childhood tumor. Relapsed or refractory neuroblastoma has a very poor prognosis despite recent treatment advances. To investigate genomic alterations associated with relapse and therapy resistance, whole-genome sequencing was performed on diagnostic and relapsed lesions together with constitutional DNA from seven children. Sequencing of relapsed tumors indicates somatic alterations in diverse genes, including those involved in RAS-MAPK signaling, promoting cell cycle progression or function in telomere maintenance and immortalization. Among recurrent alterations, CCND1-gain, TERT-rearrangements, and point mutations in POLR2A, CDK5RAP, and MUC16 were shown in ≥ 2 individuals. Our cohort contained examples of converging genomic alterations in primary-relapse tumor pairs, indicating dependencies related to specific genetic lesions. We also detected rare genetic germline variants in DNA repair genes (e.g., BARD1, BRCA2, CHEK2, and WRN) that might cooperate with somatically acquired variants in these patients with highly aggressive recurrent neuroblastoma. Our data indicate the importance of monitoring recurrent neuroblastoma through sequential genomic characterization and that new therapeutic approaches combining the targeting of MAPK signaling, cell cycle progression, and telomere activity are required for this challenging patient group.

scholarly journals Investigation and Functional Enrichment Analysis of the Human Host Interaction Network with Common Gram-Negative Respiratory Pathogens Predicts Possible Association with Lung Adenocarcinoma

2021 ◽  
Vol 28 (1) ◽  
pp. 20-33
Author(s):  
Lydia-Eirini Giannakou ◽  
Athanasios-Stefanos Giannopoulos ◽  
Chrissi Hatzoglou ◽  
Konstantinos I. Gourgoulianis ◽  
Erasmia Rouka ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Interaction Network ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Functional Enrichment ◽  
Cell Junctions ◽  
Respiratory Pathogens ◽  
Gram Negative ◽  
Human Proteins ◽  
Apoptotic Pathways

Haemophilus influenzae (Hi), Moraxella catarrhalis (MorCa) and Pseudomonas aeruginosa (Psa) are three of the most common gram-negative bacteria responsible for human respiratory diseases. In this study, we aimed to identify, using the functional enrichment analysis (FEA), the human gene interaction network with the aforementioned bacteria in order to elucidate the full spectrum of induced pathogenicity. The Human Pathogen Interaction Database (HPIDB 3.0) was used to identify the human proteins that interact with the three pathogens. FEA was performed via the ToppFun tool of the ToppGene Suite and the GeneCodis database so as to identify enriched gene ontologies (GO) of biological processes (BP), cellular components (CC) and diseases. In total, 11 human proteins were found to interact with the bacterial pathogens. FEA of BP GOs revealed associations with mitochondrial membrane permeability relative to apoptotic pathways. FEA of CC GOs revealed associations with focal adhesion, cell junctions and exosomes. The most significantly enriched annotations in diseases and pathways were lung adenocarcinoma and cell cycle, respectively. Our results suggest that the Hi, MorCa and Psa pathogens could be related to the pathogenesis and/or progression of lung adenocarcinoma via the targeting of the epithelial cellular junctions and the subsequent deregulation of the cell adhesion and apoptotic pathways. These hypotheses should be experimentally validated.

scholarly journals Caenorhabditis elegans SMG-2 Selectively Marks mRNAs Containing Premature Translation Termination Codons

2007 ◽  
Vol 27 (16) ◽  
pp. 5630-5638 ◽  
Author(s):  
Lisa Johns ◽  
Andrew Grimson ◽  
Sherry L. Kuchma ◽  
Carrie Loushin Newman ◽  
Philip Anderson
Keyword(s):  
Caenorhabditis Elegans ◽  
Mammalian Cells ◽  
Translation Termination ◽  
Yeast Two Hybrid ◽  
Eukaryotic Mrnas ◽  
Nonsense Mediated Mrna Decay ◽  
Endogenous Genes ◽  
Alternatively Spliced ◽  
Two Hybrid ◽  
Premature Translation Termination

ABSTRACT Eukaryotic mRNAs containing premature translation termination codons (PTCs) are rapidly degraded by a process termed “nonsense-mediated mRNA decay” (NMD). We examined protein-protein and protein-RNA interactions among Caenorhabditis elegans proteins required for NMD. SMG-2, SMG-3, and SMG-4 are orthologs of yeast (Saccharomyces cerevisiae) and mammalian Upf1, Upf2, and Upf3, respectively. A combination of immunoprecipitation and yeast two-hybrid experiments indicated that SMG-2 interacts with SMG-3, SMG-3 interacts with SMG-4, and SMG-2 interacts indirectly with SMG-4 via shared interactions with SMG-3. Such interactions are similar to those observed in yeast and mammalian cells. SMG-2-SMG-3-SMG-4 interactions require neither SMG-2 phosphorylation, which is abolished in smg-1 mutants, nor SMG-2 dephosphorylation, which is reduced or eliminated in smg-5 mutants. SMG-2 preferentially associates with PTC-containing mRNAs. We monitored the association of SMG-2, SMG-3, and SMG-4 with mRNAs of five endogenous genes whose mRNAs are alternatively spliced to either contain or not contain PTCs. SMG-2 associates with both PTC-free and PTC-containing mRNPs, but it strongly and preferentially associates with (“marks”) those containing PTCs. SMG-2 marking of PTC-mRNPs is enhanced by SMG-3 and SMG-4, but SMG-3 and SMG-4 are not detectably associated with the same mRNPs. Neither SMG-2 phosphorylation nor dephosphorylation is required for selective association of SMG-2 with PTC-containing mRNPs, indicating that SMG-2 is phosphorylated only after premature terminations have been discriminated from normal terminations. We discuss these observations with regard to the functions of SMG-2 and its phosphorylation during NMD.

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