The multiple lives of DEAD-box RNA helicase DP103/DDX20/Gemin3

2018 ◽  
Vol 46 (2) ◽  
pp. 329-341 ◽  
Author(s):  
Frank Curmi ◽  
Ruben J. Cauchi
Keyword(s):  
Rna Binding ◽  
Muscular Atrophy ◽  
Essential Gene ◽  
Rna Helicase ◽  
Survival Motor Neuron ◽  
In Vivo Studies ◽  
Critical Function ◽  
Dead Box ◽  
Small Nuclear Ribonucleoprotein

Gemin3, also known as DDX20 or DP103, is a DEAD-box RNA helicase which is involved in more than one cellular process. Though RNA unwinding has been determined in vitro, it is surprisingly not required for all of its activities in cellular metabolism. Gemin3 is an essential gene, present in Amoeba and Metazoa. The highly conserved N-terminus hosts the helicase core, formed of the helicase- and DEAD-domains, which, based on crystal structure determination, have key roles in RNA binding. The C-terminus of Gemin3 is highly divergent between species and serves as the interaction site for several accessory factors that could recruit Gemin3 to its target substrates and/or modulate its function. This review article focuses on the known roles of Gemin3, first as a core member of the survival motor neuron (SMN) complex, in small nuclear ribonucleoprotein biogenesis. Although mechanistic details are lacking, a critical function for Gemin3 in this pathway is supported by numerous in vitro and in vivo studies. Gene expression activities of Gemin3 are next underscored, mainly messenger ribonucleoprotein trafficking, gene silencing via microRNA processing, and transcriptional regulation. The involvement of Gemin3 in abnormal cell signal transduction pathways involving p53 and NF-κB is also highlighted. Finally, the clinical implications of Gemin3 deregulation are discussed including links to spinal muscular atrophy, poliomyelitis, amyotrophic lateral sclerosis, and cancer. Impressive progress made over the past two decades since the discovery of Gemin3 bodes well for further work that refines the mechanism(s) underpinning its multiple activities.

The Escherichia coli RNA degradosome: structure, function and relationship to other ribonucleolytic multienyzme complexes

2002 ◽  
Vol 30 (2) ◽  
pp. 150-155 ◽  
Author(s):  
A. J. Carpousis
Keyword(s):  
Escherichia Coli ◽  
Rna Binding ◽  
Intrinsic Property ◽  
Rna Helicase ◽  
Rnase E ◽  
E Coli ◽  
Ribonucleolytic Activity ◽  
Dead Box ◽  
Rna Degradosome

mRNA instability is an intrinsic property that permits timely changes in gene expression by limiting the lifetime of a transcript. The RNase E of Escherichia coli is a single-strand-specific endonuclease involved in the processing of rRNA and the degradation of mRNA. A nucleolytic multienzyme complex now known as the RNA degradosome was discovered during the purification and characterization of RNase E. Two other components are a 3′ exoribonuclease (polynucleotide phosphorylase, PNPase) and a DEAD-box RNA helicase (RNA helicase B, RhlB). RNase E is a large multidomain protein with N-terminal ribonucleolytic activity, an RNA-binding domain and a C-terminal ‘scaffold’ that binds PNPase, enolase and RhlB. RhlB by itself has little activity but is strongly stimulated by its interaction with RNase E. RhlB in vitro can facilitate the degradation of structured RNA by PNPase. Since the discovery of the RNA degradosome in E. coli, related complexes have been described in other organisms.

scholarly journals The DEAD-box RNA helicase Ded1 from yeast is associated with the signal recognition particle (SRP), and its enzymatic activity is regulated by SRP21

2020 ◽  
Author(s):  
Hilal Yeter-Alat ◽  
Naïma Belgareh-Touzé ◽  
Emmeline Huvelle ◽  
Molka Mokdadi ◽  
Josette Banroques ◽  
...  
Keyword(s):  
Enzymatic Activity ◽  
Rna Binding ◽  
Signal Recognition Particle ◽  
Rna Helicase ◽  
Signal Recognition ◽  
Dead Box ◽  
Enzymatic Regulation ◽  
The Dead

ABSTRACTThe DEAD-box RNA helicase Ded1 is an essential yeast protein involved in translation initiation. It belongs to the DDX3 subfamily of proteins implicated in developmental and cell-cycle regulation. In vitro, the purified Ded1 protein is an ATP-dependent RNA binding protein and an RNA-dependent ATPase, but it lacks RNA substrate specificity and enzymatic regulation. Here we demonstrate by yeast genetics, in situ localization and in vitro biochemical approaches that Ded1 is associated with, and regulated by, the signal recognition particle (SRP), which is a universally conserved ribonucleoprotein complex required for the co-translational translocation of polypeptides into the endoplasmic reticulum lumen and membrane. Ded1 is physically associated with SRP components in vivo and in vitro. Ded1 is genetically linked with SRP proteins. Finally, the enzymatic activity of Ded1 is inhibited by SRP21 with SCR1 RNA. We propose a model where Ded1 actively participates in the translocation of proteins during translation. Our results open a new comprehension of the cellular role of Ded1 during translation.

scholarly journals Gemin3 Is an Essential Gene Required for Larval Motor Function and Pupation in Drosophila

2009 ◽  
Vol 20 (1) ◽  
pp. 90-101 ◽  
Author(s):  
Karl B. Shpargel ◽  
Kavita Praveen ◽  
T. K. Rajendra ◽  
A. Gregory Matera
Keyword(s):  
Protein Function ◽  
Muscular Atrophy ◽  
Essential Gene ◽  
Survival Motor Neuron ◽  
Loss Of Function ◽  
Transposon Insertion ◽  
Associated Proteins ◽  
Smn Protein

The assembly of metazoan Sm-class small nuclear ribonucleoproteins (snRNPs) is an elaborate, step-wise process that takes place in multiple subcellular compartments. The initial steps, including formation of the core RNP, are mediated by the survival motor neuron (SMN) protein complex. Loss-of-function mutations in human SMN1 result in a neuromuscular disease called spinal muscular atrophy. The SMN complex is comprised of SMN and a number of tightly associated proteins, collectively called Gemins. In this report, we identify and characterize the fruitfly ortholog of the DEAD box protein, Gemin3. Drosophila Gemin3 (dGem3) colocalizes and interacts with dSMN in vitro and in vivo. RNA interference for dGem3 codepletes dSMN and inhibits efficient Sm core assembly in vitro. Transposon insertion mutations in Gemin3 are larval lethals and also codeplete dSMN. Transgenic overexpression of dGem3 rescues lethality, but overexpression of dSMN does not, indicating that loss of dSMN is not the primary cause of death. Gemin3 mutant larvae exhibit motor defects similar to previously characterized Smn alleles. Remarkably, appreciable numbers of Gemin3 mutants (along with one previously undescribed Smn allele) survive as larvae for several weeks without pupating. Our results demonstrate the conservation of Gemin3 protein function in metazoan snRNP assembly and reveal that loss of either Smn or Gemin3 can contribute to neuromuscular dysfunction.

scholarly journals RNA Helicase A Regulates the Replication of RNA Viruses

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 361
Author(s):  
Rui-Zhu Shi ◽  
Yuan-Qing Pan ◽  
Li Xing
Keyword(s):  
Virus Replication ◽  
Rna Binding ◽  
Rna Viruses ◽  
Rna Helicase ◽  
Rna Helicase A ◽  
Double Stranded Rna ◽  
Binding Domains ◽  
N Terminus

The RNA helicase A (RHA) is a member of DExH-box helicases and characterized by two double-stranded RNA binding domains at the N-terminus. RHA unwinds double-stranded RNA in vitro and is involved in RNA metabolisms in the cell. RHA is also hijacked by a variety of RNA viruses to facilitate virus replication. Herein, this review will provide an overview of the role of RHA in the replication of RNA viruses.

scholarly journals The RNA Binding Protein hnRNP Q Modulates the Utilization of Exon 7 in the Survival Motor Neuron 2 (SMN2) Gene

2008 ◽  
Vol 28 (22) ◽  
pp. 6929-6938 ◽  
Author(s):  
Hung-Hsi Chen ◽  
Jan-Growth Chang ◽  
Ruei-Min Lu ◽  
Tsui-Yi Peng ◽  
Woan-Yuh Tarn
Keyword(s):  
Rna Binding ◽  
Muscular Atrophy ◽  
Rna Binding Protein ◽  
Neuromuscular Disorder ◽  
Mrna Splicing ◽  
Survival Motor Neuron ◽  
Smn2 Gene ◽  
Smn Protein ◽  
High Level ◽  
Precursor Mrna

ABSTRACT Spinal muscular atrophy (SMA) is a recessive neuromuscular disorder caused by the homozygous loss of the SMN1 gene. The human SMN2 gene has a C-to-T transition at position +6 of exon 7 and thus produces exon 7-skipping mRNAs. However, we observed an unexpectedly high level of exon 7-containing SMN2 transcripts as well as SMN protein in testis of smn −/− SMN2 transgenic mice. Using affinity chromatography, we identified several SMN RNA-associating proteins in mouse testis and human HeLa cells, including hnRNP Q. The major hnRNP Q isoform, Q1, directly bound SMN exon 7 in the vicinity of nucleotide +6. Overexpression of hnRNP Q1 promoted the inclusion of exon 7 in SMN2, probably by activating the use of its upstream 3′ splice site. However, the minor isoforms Q2/Q3 could antagonize the activity of hnRNP Q1 and induced exon 7 exclusion. Intriguingly, enhanced exon 7 inclusion was also observed upon concomitant depletion of three hnRNP Q isoforms. Thus, differential expression of hnRNP Q isoforms may result in intricate control of SMN precursor mRNA splicing. Here, we demonstrate that hnRNP Q is a splicing modulator of SMN, further underscoring the potential of hnRNP Q as a therapeutic target for SMA.

scholarly journals The Emerging Role and Promise of Circular RNAs in Obesity and Related Metabolic Disorders

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1473
Author(s):  
Mohamed Zaiou
Keyword(s):  
Rna Binding ◽  
Metabolic Diseases ◽  
Rna Binding Proteins ◽  
In Vivo Studies ◽  
Future Research ◽  
Circular Rnas ◽  
Exciting Field ◽  
Rna Molecules

Circular RNAs (circRNAs) are genome transcripts that are produced from back-splicing of specific regions of pre-mRNA. These single-stranded RNA molecules are widely expressed across diverse phyla and many of them are stable and evolutionary conserved between species. Growing evidence suggests that many circRNAs function as master regulators of gene expression by influencing both transcription and translation processes. Mechanistically, circRNAs are predicted to act as endogenous microRNA (miRNA) sponges, interact with functional RNA-binding proteins (RBPs), and associate with elements of the transcriptional machinery in the nucleus. Evidence is mounting that dysregulation of circRNAs is closely related to the occurrence of a range of diseases including cancer and metabolic diseases. Indeed, there are several reports implicating circRNAs in cardiovascular diseases (CVD), diabetes, hypertension, and atherosclerosis. However, there is very little research addressing the potential role of these RNA transcripts in the occurrence and development of obesity. Emerging data from in vitro and in vivo studies suggest that circRNAs are novel players in adipogenesis, white adipose browning, obesity, obesity-induced inflammation, and insulin resistance. This study explores the current state of knowledge on circRNAs regulating molecular processes associated with adipogenesis and obesity, highlights some of the challenges encountered while studying circRNAs and suggests some perspectives for future research directions in this exciting field of study.

scholarly journals Fourteen Residues of the U1 snRNP-Specific U1A Protein Are Required for Homodimerization, Cooperative RNA Binding, and Inhibition of Polyadenylation

2000 ◽  
Vol 20 (6) ◽  
pp. 2209-2217 ◽  
Author(s):  
Jacqueline M. T. Klein Gunnewiek ◽  
Reem I. Hussein ◽  
Yvonne van Aarssen ◽  
Daphne Palacios ◽  
Rob de Jong ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Rna Binding ◽  
Structural Data ◽  
Protein Molecule ◽  
Cooperative Binding ◽  
Mobility Shift ◽  
Small Nuclear Ribonucleoprotein ◽  
U1a Protein

ABSTRACT It was previously shown that the human U1A protein, one of three U1 small nuclear ribonucleoprotein-specific proteins, autoregulates its own production by binding to and inhibiting the polyadenylation of its own pre-mRNA. The U1A autoregulatory complex requires two molecules of U1A protein to cooperatively bind a 50-nucleotide polyadenylation-inhibitory element (PIE) RNA located in the U1A 3′ untranslated region. Based on both biochemical and nuclear magnetic resonance structural data, it was predicted that protein-protein interactions between the N-terminal regions (amino acids [aa] 1 to 115) of the two U1A proteins would form the basis for cooperative binding to PIE RNA and for inhibition of polyadenylation. In this study, we not only experimentally confirmed these predictions but discovered some unexpected features of how the U1A autoregulatory complex functions. We found that the U1A protein homodimerizes in the yeast two-hybrid system even when its ability to bind RNA is incapacitated. U1A dimerization requires two separate regions, both located in the N-terminal 115 residues. Using both coselection and gel mobility shift assays, U1A dimerization was also observed in vitro and found to depend on the same two regions that were found in vivo. Mutation of the second homodimerization region (aa 103 to 115) also resulted in loss of inhibition of polyadenylation and loss of cooperative binding of two U1A protein molecules to PIE RNA. This same mutation had no effect on the binding of one U1A protein molecule to PIE RNA. A peptide containing two copies of aa 103 to 115 is a potent inhibitor of polyadenylation. Based on these data, a model of the U1A autoregulatory complex is presented.

Phosphorylation of threonine 204 of DEAD-box RNA helicase DDX3 by cyclin B/cdc2 in vitro

2007 ◽  
Vol 356 (3) ◽  
pp. 668-673 ◽  
Author(s):  
Takeshi Sekiguchi ◽  
Yoshiko Kurihara ◽  
Junko Fukumura
Keyword(s):  
Rna Helicase ◽  
Cyclin B ◽  
Dead Box

scholarly journals The DEAD-box RNA helicase 5 positively regulates the replication of porcine reproductive and respiratory syndrome virus by interacting with viral Nsp9 in vitro

2015 ◽  
Vol 195 ◽  
pp. 217-224 ◽  
Author(s):  
Shuangcheng Zhao ◽  
Xinna Ge ◽  
Xiaolong Wang ◽  
Aijing Liu ◽  
Xin Guo ◽  
...  
Keyword(s):  
Rna Helicase ◽  
Respiratory Syndrome Virus ◽  
Dead Box ◽  
The Dead

scholarly journals The role of RNA metabolism in neurological diseases

2015 ◽  
Vol 18 (2) ◽  
pp. 5-14 ◽  
Author(s):  
AM Alaqeel ◽  
H Abou Al-Shaar ◽  
RK Shariff ◽  
A Albakr
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Muscular Atrophy ◽  
Neurological Diseases ◽  
Rna Metabolism ◽  
Molecular Pathogenesis ◽  
Survival Motor Neuron ◽  
Major Morbidity ◽  
Rna Translation

Abstract Neurodegenerative disorders are commonly encountered in medical practices. Such diseases can lead to major morbidity and mortality among the affected individuals. The molecular pathogenesis of these disorders is not yet clear. Recent literature has revealed that mutations in RNA-binding proteins are a key cause of several human neuronal-based diseases. This review discusses the role of RNA metabolism in neurological diseases with specific emphasis on roles of RNA translation and microRNAs in neurodegeneration, RNA-mediated toxicity, repeat expansion diseases and RNA metabolism, molecular pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia, and neurobiology of survival motor neuron (SMN) and spinal muscular atrophy.

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