scholarly journals SINEUP long non-coding RNA acts via PTBP1 and HNRNPK to promote translational initiation assemblies

2019 ◽  
Author(s):  
Naoko Toki ◽  
Hazuki Takahashi ◽  
Silvia Zucchelli ◽  
Stefano Gustincich ◽  
Piero Carninci
Keyword(s):  
Translational Regulation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Mrna Translation ◽  
Protein Translation ◽  
Expression Vectors ◽  
Translational Initiation ◽  
Target Mrna ◽  
Target Mrnas ◽  
Wide Range

AbstractSINEUPs are long non-coding RNAs (lncRNAs) that contain a SINE element, which up-regulate the translation of target mRNA and have been studied in a wide range of applications for biological and therapeutic tools, although the molecular mechanism is unclear. Here, we focused on the kinetic distribution of target mRNAs and SINEUP RNAs by performing co-transfection of expression vectors for these transcripts into human embryonic normal kidney cells (HEK293T/17) to investigate the network of translational regulation. The results showed that co-localization of target mRNAs and SINEUP RNAs in the cytoplasm was one of the key phenomena. We identified PTBP1 and HNRNPK as essential RNA binding proteins. These proteins contributed to SINEUP RNA sub-cellular distribution and to assembly of translational initiation complexes, leading to enhanced target mRNA translation. These findings will promote a better understanding of the mechanisms on the fate of regulatory RNAs implicated in efficient protein translation.

scholarly journals SINEUP long non-coding RNA acts via PTBP1 and HNRNPK to promote translational initiation assemblies

2020 ◽  
Vol 48 (20) ◽  
pp. 11626-11644
Author(s):  
Naoko Toki ◽  
Hazuki Takahashi ◽  
Harshita Sharma ◽  
Matthew N Z Valentine ◽  
Ferdous-Ur M Rahman ◽  
...  
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Mrna Translation ◽  
Protein Translation ◽  
Expression Vectors ◽  
Cellular Distribution ◽  
Translational Initiation ◽  
Target Mrna ◽  
Target Mrnas ◽  
Wide Range

Abstract SINEUPs are long non-coding RNAs (lncRNAs) that contain a SINE element, and which up-regulate the translation of target mRNA. They have been studied in a wide range of applications, as both biological and therapeutic tools, although the underpinning molecular mechanism is unclear. Here, we focused on the sub-cellular distribution of target mRNAs and SINEUP RNAs, performing co-transfection of expression vectors for these transcripts into human embryonic kidney cells (HEK293T/17), to investigate the network of translational regulation. The results showed that co-localization of target mRNAs and SINEUP RNAs in the cytoplasm was a key phenomenon. We identified PTBP1 and HNRNPK as essential RNA binding proteins. These proteins contributed to SINEUP RNA sub-cellular distribution and to assembly of translational initiation complexes, leading to enhanced target mRNA translation. These findings will promote a better understanding of the mechanisms employed by regulatory RNAs implicated in efficient protein translation.

scholarly journals The YTHDF proteins ECT2 and ECT3 bind largely overlapping target sets and influence target mRNA abundance, not alternative polyadenylation

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Laura Arribas-Hernández ◽  
Sarah Rennie ◽  
Michael Schon ◽  
Carlotta Porcelli ◽  
Balaji Enugutti ◽  
...  
Keyword(s):  
Indirect Effects ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Expression Profiles ◽  
Alternative Polyadenylation ◽  
Target Mrna ◽  
Target Mrnas ◽  
Yth Domain ◽  
Target Sets

Gene regulation via N6-methyladenosine (m6A) in mRNA involves RNA-binding proteins that recognize m6A via a YT521-B homology (YTH) domain. The plant YTH domain proteins ECT2 and ECT3 act genetically redundantly in stimulating cell proliferation during organogenesis, but several fundamental questions regarding their mode of action remain unclear. Here, we use HyperTRIBE (targets of RNA-binding proteins identified by editing) to show that most ECT2 and ECT3 targets overlap, with only few examples of preferential targeting by either of the two proteins. HyperTRIBE in different mutant backgrounds also provides direct views of redundant and specific target interactions of the two proteins. We also show that contrary to conclusions of previous reports, ECT2 does not accumulate in the nucleus. Accordingly, inactivation of ECT2, ECT3 and their surrogate ECT4 does not change patterns of polyadenylation site choice in ECT2/3 target mRNAs, but does lead to lower steady state accumulation of target mRNAs. In addition, mRNA and microRNA expression profiles show indications of stress response activation in ect2/ect3/ect4 mutants, likely via indirect effects. Thus, previous suggestions of control of alternative polyadenylation by ECT2 are not supported by evidence, and ECT2 and ECT3 act largely redundantly to regulate target mRNA, including its abundance, in the cytoplasm.

scholarly journals Evidence That Ternary Complex (eIF2-GTP-tRNAi Met)–Deficient Preinitiation Complexes Are Core Constituents of Mammalian Stress Granules

2002 ◽  
Vol 13 (1) ◽  
pp. 195-210 ◽  
Author(s):  
Nancy Kedersha ◽  
Samantha Chen ◽  
Natalie Gilks ◽  
Wei Li ◽  
Ira J. Miller ◽  
...  
Keyword(s):  
Ternary Complex ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Stress Granules ◽  
Direct Consequence ◽  
Protein Translation ◽  
Preinitiation Complex ◽  
Translational Initiation ◽  
Stressed Cells ◽  
As Stress

Environmental stress-induced phosphorylation of eIF2α inhibits protein translation by reducing the availability of eIF2-GTP-tRNAiMet, the ternary complex that joins initiator tRNAMet to the 43S preinitiation complex. The resulting untranslated mRNA is dynamically routed to discrete cytoplasmic foci known as stress granules (SGs), a process requiring the related RNA-binding proteins TIA-1 and TIAR. SGs appear to be in equilibrium with polysomes, but the nature of this relationship is obscure. We now show that most components of the 48S preinitiation complex (i.e., small, but not large, ribosomal subunits, eIF3, eIF4E, eIF4G) are coordinately recruited to SGs in arsenite-stressed cells. In contrast, eIF2 is not a component of newly assembled SGs. Cells expressing a phosphomimetic mutant (S51D) of eIF2α assemble SGs of similar composition, confirming that the recruitment of these factors is a direct consequence of blocked translational initiation and not due to other effects of arsenite. Surprisingly, phospho-eIF2α is recruited to SGs that are disassembling in cells recovering from arsenite-induced stress. We discuss these results in the context of a translational checkpoint model wherein TIA and eIF2 are functional antagonists of translational initiation, and in which lack of ternary complex drives SG assembly.

scholarly journals Translational regulation of Chk1 expression by eIF3a via interaction with the RNA-binding protein HuR

2020 ◽  
Vol 477 (10) ◽  
pp. 1939-1950 ◽  
Author(s):  
Zizheng Dong ◽  
Jianguo Liu ◽  
Jian-Ting Zhang
Keyword(s):  
Translational Regulation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Regulatory Function ◽  
Rna Recognition Motif ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation

eIF3a is a putative subunit of the eukaryotic translation initiation factor 3 complex. Accumulating evidence suggests that eIF3a may have a translational regulatory function by suppressing translation of a subset of mRNAs while accelerating that of other mRNAs. Albeit the suppression of mRNA translation may derive from eIF3a binding to the 5′-UTRs of target mRNAs, how eIF3a may accelerate mRNA translation remains unknown. In this study, we show that eIF3a up-regulates translation of Chk1 but not Chk2 mRNA by interacting with HuR, which binds directly to the 3′-UTR of Chk1 mRNA. The interaction between eIF3a and HuR occurs at the 10-amino-acid repeat domain of eIF3a and the RNA recognition motif domain of HuR. This interaction may effectively circularize Chk1 mRNA to form an end-to-end complex that has recently been suggested to accelerate mRNA translation. Together with previous findings, we conclude that eIF3a may regulate mRNA translation by directly binding to the 5′-UTR to suppress or by interacting with RNA-binding proteins at 3′-UTRs to accelerate mRNA translation.

scholarly journals The regulation of protein translation and its implications for cancer

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Ping Song ◽  
Fan Yang ◽  
Hongchuan Jin ◽  
Xian Wang
Keyword(s):  
Translation Initiation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Noncoding Rnas ◽  
Mrna Translation ◽  
Protein Translation ◽  
Initiation Factors ◽  
Translation Initiation Factors ◽  
Precision Therapy ◽  
Novel Approaches

AbstractIn addition to the deregulation of gene transcriptions and post-translational protein modifications, the aberrant translation from mRNAs to proteins plays an important role in the pathogenesis of various cancers. Targeting mRNA translation are expected to become potential approaches for anticancer treatments. Protein translation is affected by many factors including translation initiation factors and RNA-binding proteins. Recently, modifications of mRNAs mainly N6-methyladenine (m6A) modification and noncoding RNAs, such as microRNAs and long noncoding RNAs are involved. In this review, we generally summarized the recent advances on the regulation of protein translation by the interplay between mRNA modifications and ncRNAs. By doing so, we hope this review could offer some hints for the development of novel approaches in precision therapy of human cancers.

scholarly journals The Arabidopsis m6A-binding proteins ECT2 and ECT3 bind largely overlapping mRNA target sets and influence target mRNA abundance, not alternative polyadenylation

2021 ◽  
Author(s):  
Peter Brodersen ◽  
Laura Arribas-Hernández ◽  
Sarah Rennie ◽  
Michael Schon ◽  
Carlotta Porcelli ◽  
...  
Keyword(s):  
Indirect Effects ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Expression Profiles ◽  
Alternative Polyadenylation ◽  
Target Mrna ◽  
Target Mrnas ◽  
Yth Domain ◽  
Target Sets

Gene regulation via N6-methyladenosine (m6A) in mRNA involves RNA-binding proteins that recognize m6A via a YT521-B homology (YTH) domain. The plant YTH domain proteins ECT2 and ECT3 act genetically redundantly in stimulating cell proliferation during organogenesis, but several fundamental questions regarding their mode of action remain unclear. Here, we use HyperTRIBE (targets of RNA-binding proteins identified by editing) to show that most ECT2 and ECT3 targets overlap, with only few examples of preferential targeting by either of the two proteins. HyperTRIBE in different mutant backgrounds also provides direct views of redundant and specific target interactions of the two proteins. We also show that contrary to conclusions of previous reports, ECT2 does not accumulate in the nucleus. Accordingly, inactivation of ECT2, ECT3 and their surrogate ECT4 does not change patterns of polyadenylation site choice in ECT2/3 target mRNAs, but does lead to lower steady state accumulation of target mRNAs. In addition, mRNA and microRNA expression profiles show indications of stress response activation in ect2/ect3/ect4 mutants, likely via indirect effects. Thus, previous suggestions of control of alternative polyadenylation by ECT2 are not supported by evidence, and ECT2 and ECT3 act largely redundantly to regulate target mRNA, including its abundance, in the cytoplasm.

The Musashi family RNA-binding proteins in stem cells

2010 ◽  
Vol 1 (1) ◽  
pp. 59-66 ◽  
Author(s):  
Kenichi Horisawa ◽  
Takao Imai ◽  
Hideyuki Okano ◽  
Hiroshi Yanagawa
Keyword(s):  
Progenitor Cells ◽  
Translational Regulation ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Regulatory Pathways ◽  
Target Mrnas ◽  
Action Mechanisms ◽  
Neural Stem Progenitor Cells ◽  
Novel Target

AbstractThe Musashi family is an evolutionarily conserved group of RNA-binding proteins. In mammal, two members of the group, Msi1 and Msi2, have been identified to date. Msi1 is considered to play roles in maintaining the stem cell status (stemness) of neural stem/progenitor cells in adults and in the development of central nervous system through translational regulation of its target mRNAs, which encode regulators of signal transduction and the cell cycle. Recently, strong expression of Msi1 in various somatic stem/progenitor cells of adult tissues, such as eye, gut, stomach, breast, and hair follicle, has been reported. The protein is also expressed in various cancer cells, and ectopically emerging cells have been found in neural tissues of patients with diseases involving neural disorder, including epilepsy. Many novel target mRNAs and regulatory pathways of Msi1 have been reported in recent years. Here, we present a review of the functions and action mechanisms of Msi1 protein and discuss possible directions for further study.

scholarly journals The DAZL and PABP families: RNA-binding proteins with interrelated roles in translational control in oocytes

Reproduction ◽  
2009 ◽  
Vol 137 (4) ◽  
pp. 595-617 ◽  
Author(s):  
Matthew Brook ◽  
Joel W S Smith ◽  
Nicola K Gray
Keyword(s):  
Gene Expression ◽  
Germ Cells ◽  
Translational Control ◽  
Translational Regulation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Regulation Of Gene Expression ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor

Gametogenesis is a highly complex process that requires the exquisite temporal, spatial and amplitudinal regulation of gene expression at multiple levels. Translational regulation is important in a wide variety of cell types but may be even more prevalent in germ cells, where periods of transcriptional quiescence necessitate the use of post-transcriptional mechanisms to effect changes in gene expression. Consistent with this, studies in multiple animal models have revealed an essential role for mRNA translation in the establishment and maintenance of reproductive competence. While studies in humans are less advanced, emerging evidence suggests that translational regulation plays a similarly important role in human germ cells and fertility. This review highlights specific mechanisms of translational regulation that play critical roles in oogenesis by activating subsets of mRNAs. These mRNAs are activated in a strictly determined temporal manner via elements located within their 3′UTR, which serve as binding sites fortrans-acting factors. While we concentrate on oogenesis, these regulatory events also play important roles during spermatogenesis. In particular, we focus on the deleted in azoospermia-like (DAZL) family of proteins, recently implicated in the translational control of specific mRNAs in germ cells; their relationship with the general translation initiation factor poly(A)-binding protein (PABP) and the process of cytoplasmic mRNA polyadenylation.

scholarly journals The Bic-C Family of Developmental Translational Regulators

2012 ◽  
Vol 2012 ◽  
pp. 1-23 ◽  
Author(s):  
Chiara Gamberi ◽  
Paul Lasko
Keyword(s):  
Developmental Biology ◽  
Human Disease ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Mrna Translation ◽  
Protein Translation ◽  
Model Organisms ◽  
Founding Member ◽  
Evolutionarily Conserved ◽  
Translational Regulators

Regulation of mRNA translation is especially important during cellular and developmental processes. Many evolutionarily conserved proteins act in the context of multiprotein complexes and modulate protein translation both at the spatial and the temporal levels. Among these, Bicaudal C constitutes a family of RNA binding proteins whose founding member was first identified inDrosophilaand contains orthologs in vertebrates. We discuss recent advances towards understanding the functions of these proteins in the context of the cellular and developmental biology of many model organisms and their connection to human disease.

The Therapeutic Potential and Role of miRNA, lncRNA, and circRNA in Osteoarthritis

2019 ◽  
Vol 19 (4) ◽  
pp. 255-263 ◽  
Author(s):  
Yuangang Wu ◽  
Xiaoxi Lu ◽  
Bin Shen ◽  
Yi Zeng
Keyword(s):  
Gene Expression ◽  
Gene Therapy ◽  
Extracellular Matrix ◽  
Inflammatory Reaction ◽  
Noncoding Rna ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Protein Translation ◽  
Cochrane Library

Background: Osteoarthritis (OA) is a disease characterized by progressive degeneration, joint hyperplasia, narrowing of joint spaces, and extracellular matrix metabolism. Recent studies have shown that the pathogenesis of OA may be related to non-coding RNA, and its pathological mechanism may be an effective way to reduce OA. Objective: The purpose of this review was to investigate the recent progress of miRNA, long noncoding RNA (lncRNA) and circular RNA (circRNA) in gene therapy of OA, discussing the effects of this RNA on gene expression, inflammatory reaction, apoptosis and extracellular matrix in OA. Methods: The following electronic databases were searched, including PubMed, EMBASE, Web of Science, and the Cochrane Library, for published studies involving the miRNA, lncRNA, and circRNA in OA. The outcomes included the gene expression, inflammatory reaction, apoptosis, and extracellular matrix. Results and Discussion: With the development of technology, miRNA, lncRNA, and circRNA have been found in many diseases. More importantly, recent studies have found that RNA interacts with RNA-binding proteins to regulate gene transcription and protein translation, and is involved in various pathological processes of OA, thus becoming a potential therapy for OA. Conclusion: In this paper, we briefly introduced the role of miRNA, lncRNA, and circRNA in the occurrence and development of OA and as a new target for gene therapy.

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