Ewing Sarcoma Protein: A Key Player in Human Cancer

The Ewing sarcoma protein (EWS) is a well-known player in cancer biology for the specific translocations occurring in sarcomas. The EWS-FLI1 gene fusion is the prototypical translocation that encodes the aberrant, chimeric transcription factor, which is a landmark of Ewing tumors. In all described Ewing sarcoma oncogenes, the EWS RNA binding domains are completely missing; thus RNA binding properties are not retained in the hybrid proteins. However, it is currently unknown whether the absence of EWS function in RNA metabolism plays a role in oncogenic transformation or if EWS plays a role by itself in cancer development besides its contribution to the translocation. In this regard, recent reports have highlighted an essential role for EWS in the regulation of DNA damage response (DDR), a process that counteracts genome stability and is often deregulated in cancer cells. The first part of this review will describe the structural features of EWS and its multiple roles in the regulation of gene expression, which are exerted by coordinating different steps in the synthesis and processing of pre-mRNAs. The second part will examine the role of EWS in the regulation of DDR- and cancer-related genes, with potential implications in cancer therapies. Finally, recent advances on the involvement of EWS in neuromuscular disorders will be discussed. Collectively, the information reviewed herein highlights the broad role of EWS in bridging different cellular processes and underlines the contribution of EWS to genome stability and proper cell-cycle progression in higher eukaryotic cells.

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The Role of Translation Initiation Regulation in Haematopoiesis

Comparative and Functional Genomics ◽

10.1155/2012/576540 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 7

Author(s):

Godfrey Grech ◽

Marieke von Lindern

Keyword(s):

Gene Expression ◽

Translation Initiation ◽

Translational Control ◽

Molecular Mechanisms ◽

Rna Binding ◽

Regulation Of Gene Expression ◽

Mrna Translation ◽

Translation Control ◽

Haematological Disorders

Organisation of RNAs into functional subgroups that are translated in response to extrinsic and intrinsic factors underlines a relatively unexplored gene expression modulation that drives cell fate in the same manner as regulation of the transcriptome by transcription factors. Recent studies on the molecular mechanisms of inflammatory responses and haematological disorders indicate clearly that the regulation of mRNA translation at the level of translation initiation, mRNA stability, and protein isoform synthesis is implicated in the tight regulation of gene expression. This paper outlines how these posttranscriptional control mechanisms, including control at the level of translation initiation factors and the role of RNA binding proteins, affect hematopoiesis. The clinical relevance of these mechanisms in haematological disorders indicates clearly the potential therapeutic implications and the need of molecular tools that allow measurement at the level of translational control. Although the importance of miRNAs in translation control is well recognised and studied extensively, this paper will exclude detailed account of this level of control.

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Arginine Methyltransferases as Regulators of RNA-Binding Protein Activities in Pathogenic Kinetoplastids

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.692668 ◽

2021 ◽

Vol 8 ◽

Author(s):

Gustavo D. Campagnaro ◽

Edward Nay ◽

Michael J. Plevin ◽

Angela K. Cruz ◽

Pegine B. Walrad

Keyword(s):

Gene Expression ◽

Transcriptional Control ◽

Rna Binding ◽

Methylation Status ◽

Regulation Of Gene Expression ◽

Structural Features ◽

Arginine Methylation ◽

Diverse Range ◽

Host Interaction ◽

Intronless Genes

A large number of eukaryotic proteins are processed by single or combinatorial post-translational covalent modifications that may alter their activity, interactions and fate. The set of modifications of each protein may be considered a “regulatory code”. Among the PTMs, arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), can affect how a protein interacts with other macromolecules such as nucleic acids or other proteins. In fact, many RNA-binding (RBPs) proteins are targets of PRMTs. The methylation status of RBPs may affect the expression of their bound RNAs and impact a diverse range of physiological and pathological cellular processes. Unlike most eukaryotes, Kinetoplastids have overwhelmingly intronless genes that are arranged within polycistronic units from which mature mRNAs are generated by trans-splicing. Gene expression in these organisms is thus highly dependent on post-transcriptional control, and therefore on the action of RBPs. These genetic features make trypanosomatids excellent models for the study of post-transcriptional regulation of gene expression. The roles of PRMTs in controlling the activity of RBPs in pathogenic kinetoplastids have now been studied for close to 2 decades with important advances achieved in recent years. These include the finding that about 10% of the Trypanosoma brucei proteome carries arginine methylation and that arginine methylation controls Leishmania:host interaction. Herein, we review how trypanosomatid PRMTs regulate the activity of RBPs, including by modulating interactions with RNA and/or protein complex formation, and discuss how this impacts cellular and biological processes. We further highlight unique structural features of trypanosomatid PRMTs and how it contributes to their singular functionality.

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Adaptive convergent evolution of genome proofreading in SARS-CoV2: insights into the Eigen’s paradox

10.1101/2021.09.11.459886 ◽

2021 ◽

Author(s):

Keerthic Aswin ◽

Srinivasan Ramachandran ◽

Vivek T Natarajan

Keyword(s):

Convergent Evolution ◽

Genome Stability ◽

Evolutionary History ◽

Rna Binding ◽

Phylogenetic Analyses ◽

Comparative Genome Analysis ◽

The Family ◽

History Of ◽

Key Residues

AbstractEvolutionary history of coronaviruses holds the key to understand mutational behavior and prepare for possible future outbreaks. By performing comparative genome analysis of nidovirales that contain the family of coronaviruses, we traced the origin of proofreading, surprisingly to the eukaryotic antiviral component ZNFX1. This common recent ancestor contributes two zinc finger (ZnF) motifs that are unique to viral exonuclease, segregating them from DNA proof-readers. Phylogenetic analyses indicate that following acquisition, genomes of coronaviruses retained and further fine-tuned proofreading exonuclease, whereas related families harbor substitution of key residues in ZnF1 motif concomitant to a reduction in their genome sizes. Structural modelling followed by simulation suggests the role of ZnF in RNA binding. Key ZnF residues strongly coevolve with replicase, and the helicase involved in duplex RNA unwinding. Hence, fidelity of replication in coronaviruses is a result of convergent evolution, that enables maintenance of genome stability akin to cellular proofreading systems.

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Vitamin C Transporters and Their Implications in Carcinogenesis

Nutrients ◽

10.3390/nu12123869 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3869

Author(s):

Kinga Linowiecka ◽

Marek Foksinski ◽

Anna A. Brożyna

Keyword(s):

Vitamin C ◽

Cancer Biology ◽

Redox Homeostasis ◽

Regulation Of Gene Expression ◽

Dna Demethylation ◽

Altered Expression ◽

Tet Proteins ◽

Active Dna Demethylation ◽

Hypoxic State

Vitamin C is implicated in various bodily functions due to its unique properties in redox homeostasis. Moreover, vitamin C also plays a great role in restoring the activity of 2-oxoglutarate and Fe2+ dependent dioxygenases (2-OGDD), which are involved in active DNA demethylation (TET proteins), the demethylation of histones, and hypoxia processes. Therefore, vitamin C may be engaged in the regulation of gene expression or in a hypoxic state. Hence, vitamin C has acquired great interest for its plausible effects on cancer treatment. Since its conceptualization, the role of vitamin C in cancer therapy has been a controversial and disputed issue. Vitamin C is transferred to the cells with sodium dependent transporters (SVCTs) and glucose transporters (GLUT). However, it is unknown whether the impaired function of these transporters may lead to carcinogenesis and tumor progression. Notably, previous studies have identified SVCTs’ polymorphisms or their altered expression in some types of cancer. This review discusses the potential effects of vitamin C and the impaired SVCT function in cancers. The variations in vitamin C transporter genes may regulate the active transport of vitamin C, and therefore have an impact on cancer risk, but further studies are needed to thoroughly elucidate their involvement in cancer biology.

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Role of Sp1 in insulin regulation of gene expression

Journal of Molecular Endocrinology ◽

10.1677/jme.0.0290265 ◽

2002 ◽

Vol 29 (3) ◽

pp. 265-279 ◽

Cited By ~ 110

Author(s):

SL Samson ◽

NC Wong

Keyword(s):

Intracellular Signaling ◽

Target Genes ◽

Regulation Of Gene Expression ◽

Protein A ◽

Peptide Hormone ◽

Fine Tuning ◽

Signaling Cascades ◽

Specific Interest ◽

Extracellular Signals

Sp1 is a ubiquitous nuclear factor that plays a key role in maintaining basal transcription of 'house-keeping' genes. However, recent evidence points to a more important function for Sp1 in mediating 'cross-talk' between selected signaling cascades to regulate the target genes that respond to these pathways. The role of Sp1 in mediating the actions of the peptide hormone insulin is of specific interest and serves as a model for detailing effects of intracellular signaling on Sp1 activity. This review summarizes studies suggesting that changes in Sp1 phosphorylation provide one potential mechanism for manipulating activity of this protein. A growing body of evidence reveals that the DNA binding and transcription activity of Sp1 may increase or decrease in response to changes in phosphorylation. This enables 'fine-tuning' of Sp1 activity for regulation of gene transcription. Several mechanisms exist by which Sp1 alters gene activity in response to insulin. These include independent Sp1 activity as well as collaboration or competition with others factors. This review points to an ever-increasing role for Sp1 in regulating the transcription of genes in response to extracellular signals such as insulin.

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Sequence diversity in the 3’ untranslated region of alphavirus modulates IFIT2-dependent restriction in a cell type-dependent manner

10.1101/2021.12.10.472177 ◽

2021 ◽

Author(s):

Sarah E. Hickson ◽

Eden Brekke ◽

Johannes Schwerk ◽

Indraneel Saluhke ◽

Shivam Zaver ◽

...

Keyword(s):

Untranslated Region ◽

Rna Binding ◽

Structural Features ◽

Differential Sensitivity ◽

Restriction Factor ◽

Dependent Manner ◽

Tetratricopeptide Repeats ◽

Rna Interaction

ABSTRACTAlphaviruses (family Togaviridae) are a diverse group of positive-sense RNA (+ssRNA) viruses that are transmitted by arthropods and are the causative agent of several significant human and veterinary diseases. Interferon (IFN)-induced proteins with tetratricopeptide repeats (IFITs) are a family of RNA-binding IFN stimulated genes (ISGs) that are highly upregulated following viral infection, and have been identified as potential restrictors of alphaviruses. The mechanism by which IFIT1 restricts RNA viruses is dependent on self and non-self-discrimination of RNA, and alphaviruses evade this recognition via their 5’UTR. However, the role of IFIT2 during alphavirus replication and the mechanism of viral replication inhibition is unclear. In this study, we identify IFIT2 as a restriction factor for Venezuelan equine encephalitis virus (VEEV) and show that IFIT2 binds the 3’ untranslated region (3’UTR) of the virus. We investigated the potential role of variability in the 3’UTR of the virus affecting IFIT2 antiviral activity by studying infection with VEEV. Comparison of recombinant VEEV clones containing 3’UTR sequences derived from epizootic and enzootic isolates exhibited differential sensitivity to IFIT2 restriction in vitro infection studies, suggesting that the alphavirus 3’UTR sequence may function in part to evade IFIT2 restriction. In vitro binding assays demonstrate that IFIT2 binds to the VEEV 3’UTR, however in contrast to previous studies VEEV restriction did not appear to be dependent on the ability of IFIT2 to inhibit translation of viral RNA, suggesting a novel mechanism of IFIT2 restriction. Our study demonstrates that IFIT2 is a restriction factor for alphaviruses and variability in the 3’UTR of VEEV can modulate viral restriction by IFIT2. Ongoing studies are exploring the biological consequences of IFIT2-VEEV RNA interaction in viral pathogenesis and defining sequence and structural features of RNAs that regulate IFIT2 recognition.

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SFPQ Rescues F508del-CFTR Expression and Function in Cystic Fibrosis Bronchial Epithelial Cells

10.21203/rs.3.rs-429698/v1 ◽

2021 ◽

Author(s):

Parameet Kumar ◽

Dharmendra Kumar Soni ◽

Chaitali Sen ◽

Mads B Larsen ◽

Krystyna Mazan-Mamczarz ◽

...

Keyword(s):

Cystic Fibrosis ◽

Epithelial Cells ◽

Molecular Mechanisms ◽

Rna Binding ◽

Regulation Of Gene Expression ◽

Lung Epithelial Cells ◽

Regulation Of Expression ◽

Trafficking Defects ◽

And Function

Abstract Cystic Fibrosis (CF) occurs as a result of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which lead to misfolding, trafficking defects, and impaired function of the CFTR protein. Splicing factor proline/glutamine-rich (SFPQ) is a multifunctional nuclear RNA-binding protein (RBP) implicated in the regulation of gene expression pathways and intracellular trafficking. Here, we investigated the role of SFPQ in the regulation of the expression and function of F508del-CFTR in CF lung epithelial cells. We find that the expression of SFPQ is reduced in F508del-CFTR CF epithelial cells compared to WT-CFTR control cells. Interestingly, the overexpression of SFPQ in CF cells increases the expression as well as rescues the function of F508del-CFTR. Further, comprehensive transcriptome analyses indicate that SFPQ plays a key role in activating the mutant F508del-CFTR by modulating several cellular signaling pathways. This is the first report on the role of SFPQ in the regulation of expression and function of F508del-CFTR in CF lung disease. Our findings provide new insights into SFPQ-mediated molecular mechanisms and point to possible novel epigenetic therapeutic targets for CF and related pulmonary diseases.

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The essential role of TAZ in normal tissue homeostasis

Archives of Pharmacal Research ◽

10.1007/s12272-021-01322-w ◽

2021 ◽

Vol 44 (3) ◽

pp. 253-262

Author(s):

Mi Gyeong Jeong ◽

Hyo Kyeong Kim ◽

Eun Sook Hwang

Keyword(s):

Human Cancer ◽

Structural Features ◽

Tissue Homeostasis ◽

Binding Motif ◽

Transcriptional Coactivator ◽

Functional Aspects ◽

And Migration ◽

Poor Outcomes ◽

Proliferation And Migration

AbstractTranscriptional coactivator with PDZ-binding motif (TAZ) has been extensively characterized in organ development, tissue regeneration, and tumor progression. In particular, TAZ functions as a Hippo mediator that regulates organ size, tumor growth and migration. It is highly expressed in various types of human cancer, and has been reported to be associated with tumor metastasis and poor outcomes in cancer patients, suggesting that TAZ is an oncogenic regulator. Yes-associated protein (YAP) has 60% similarity in amino acid sequence to TAZ and plays redundant roles with TAZ in the regulation of cell proliferation and migration of cancer cells. Therefore, TAZ and YAP, which are encoded by paralogous genes, are referred to as TAZ/YAP and are suggested to be functionally equivalent. Despite its similarity to YAP, TAZ can be clearly distinguished from YAP based on its genetic, structural, and functional aspects. In addition, targeting superabundant TAZ can be a promising therapeutic strategy for cancer treatment; however, persistent TAZ inactivation may cause failure of tissue homeostatic control. This review focuses primarily on TAZ, not YAP, discusses its structural features and physiological functions in the regulation of tissue homeostasis, and provides new insights into the drug development targeting TAZ to control reproductive and musculoskeletal disorders.

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The multifunctional RNA-binding protein Staufen1: an emerging regulator of oncogenesis through its various roles in key cellular events

Cellular and Molecular Life Sciences ◽

10.1007/s00018-021-03965-w ◽

2021 ◽

Author(s):

Shekoufeh Almasi ◽

Bernard J. Jasmin

Keyword(s):

Rna Binding ◽

Current Knowledge ◽

Binding Protein ◽

Neuromuscular Disorders ◽

Expression Patterns ◽

Rna Binding Protein ◽

Rna Metabolism ◽

Cancer Development ◽

Cell Functions

AbstractThe double-stranded multifunctional RNA-binding protein (dsRBP) Staufen was initially discovered in insects as a regulator of mRNA localization. Later, its mammalian orthologs have been described in different organisms, including humans. Two human orthologues of Staufen, named Staufen1 (STAU1) and Staufen2 (STAU2), share some structural and functional similarities. However, given their different spatio-temporal expression patterns, each of these orthologues plays distinct roles in cells. In the current review, we focus on the role of STAU1 in cell functions and cancer development. Since its discovery, STAU1 has mostly been studied for its involvement in various aspects of RNA metabolism. Given the pivotal role of RNA metabolism within cells, recent studies have explored the mechanistic impact of STAU1 in a wide variety of cell functions ranging from cell growth to cell death, as well as in various disease states. In particular, there has been increasing attention on the role of STAU1 in neuromuscular disorders, neurodegeneration, and cancer. Here, we provide an overview of the current knowledge on the role of STAU1 in RNA metabolism and cell functions. We also highlight the link between STAU1-mediated control of cellular functions and cancer development, progression, and treatment. Hence, our review emphasizes the potential of STAU1 as a novel biomarker and therapeutic target for cancer diagnosis and treatment, respectively.

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