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Wiley Interdisciplinary Reviews : RNA    [3 followers]  Follow    
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
     ISSN (Online) 1757-7012
     Published by John Wiley and Sons Homepage  [1594 journals]   [SJR: 2.692]   [H-I: 10]
  • Issue information
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  • The roles of DAZL in RNA biology and development
    • Abstract: RNA‐binding proteins play an important role in the regulation of gene expression by modulating translation and localization of specific messenger RNAs (mRNAs) during early development and gametogenesis. The DAZ (Deleted in Azoospermia) family of proteins, which includes DAZ, DAZL, and BOULE, are germ cell‐specific RNA‐binding proteins that are implicated in translational regulation of several transcripts. Of particular importance is DAZL, which is present in vertebrates and arose from the duplication of the ancestral BOULE during evolution. Identification of DAZL target mRNAs and characterization of the RNA‐binding sequence through in vitro binding assays and crystallographic studies revealed that DAZL binds to GUU triplets in the 3′ untranslated region of target mRNAs. Although there is compelling evidence for the role of DAZL in translation stimulation of target mRNAs, recent studies indicate that DAZL can also function in translational repression and transport of specific mRNAs. Furthermore, apart from the well‐characterized function of DAZL in gametogenesis, recent data suggest its role in early embryonic development and differentiation of pluripotent stem cells toward functional gametes. In light of the mounting evidence for the role of DAZL in various cellular and developmental processes, we summarize the currently characterized biological functions of DAZL in RNA biology and development. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors declare no potential conflict of interest.
       
  • tRNA synthetase: tRNA aminoacylation and beyond
    • Abstract: The aminoacyl‐tRNA synthetases are prominently known for their classic function in the first step of protein synthesis, where they bear the responsibility of setting the genetic code. Each enzyme is exquisitely adapted to covalently link a single standard amino acid to its cognate set of tRNA isoacceptors. These ancient enzymes have evolved idiosyncratically to host alternate activities that go far beyond their aminoacylation role and impact a wide range of other metabolic pathways and cell signaling processes. The family of aminoacyl‐tRNA synthetases has also been suggested as a remarkable scaffold to incorporate new domains that would drive evolution and the emergence of new organisms with more complex function. Because they are essential, the tRNA synthetases have served as pharmaceutical targets for drug and antibiotic development. The recent unfolding of novel important functions for this family of proteins offers new and promising pathways for therapeutic development to treat diverse human diseases. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
       
  • Degradation of oligouridylated histone mRNAs: see UUUUU and goodbye
    • Abstract: During the cell cycle the expression of replication‐dependent histones is tightly coupled to DNA synthesis. Histone messenger RNA (mRNA) levels strongly increase during early S‐phase and rapidly decrease at the end of it. Here, we review the degradation of replication‐dependent histone mRNAs, a paradigm of post‐transcriptional gene regulation, in the context of processing, translation, and oligouridylation. Replication‐dependent histone transcripts are characterized by the absence of introns and by the presence of a stem‐loop structure at the 3′ end of a very short 3′ untranslated region (UTR). These features, together with a need for active translation, are a prerequisite for their rapid decay. The degradation is induced by 3′ end additions of untemplated uridines, performed by terminal uridyl transferases. Such 3′ oligouridylated transcripts are preferentially bound by the heteroheptameric LSM1‐7 complex, which also interacts with the 3′→5′ exonuclease ERI1 (also called 3′hExo). Presumably in cooperation with LSM1‐7 and aided by the helicase UPF1, ERI1 degrades through the stem‐loop of oligouridylated histone mRNAs in repeated rounds of partial degradation and reoligouridylation. Although histone mRNA decay is now known in some detail, important questions remain open: How is ceasing nuclear DNA replication relayed to the cytoplasmic histone mRNA degradation' Why is translation important for this process' Recent research on factors such as SLIP1, DBP5, eIF3, CTIF, CBP80/20, and ERI1 has provided new insights into the 3′ end formation, the nuclear export, and the translation of histone mRNAs. We discuss how these results fit with the preparation of histone mRNAs for degradation, which starts as early as these transcripts are generated. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
       
  • Neuronal RNA‐binding proteins in health and disease
    • Abstract: In mammalian cells in general and in neurons in particular, mRNA maturation, translation, and degradation are highly complex and dynamic processes. RNA‐binding proteins (RBPs) play crucial roles in all these events. First, they participate in the choice of pre‐mRNA splice sites and in the selection of the polyadenylation sites, determining which of the possible isoforms is produced from a given precursor mRNA. Then, once in the cytoplasm, the protein composition of the RNP particles determines whether the mature mRNA is transported along the dendrites or the axon of a neuron to the synapses, how efficiently it is translated, and how stable it is. In agreement with their importance for neuronal function, mutations in genes that code for RBPs are associated with various neurological diseases. In this review, we illustrate how individual RBPs determine the fate of an mRNA, and we discuss how mutations in RBPs or perturbations of the mRNA metabolism can cause neurodegenerative disorders. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
       
  • Physiological networks and disease functions of RNA‐binding protein
           AUF1
    • Abstract: Regulated messenger RNA (mRNA) decay is an essential mechanism that governs proper control of gene expression. In fact, many of the most physiologically potent proteins are encoded by short‐lived mRNAs, many of which contain AU‐rich elements (AREs) in their 3′‐untranslated region (3′‐UTR). AREs target mRNAs for post‐transcriptional regulation, generally rapid decay, but also stabilization and translation inhibition. AREs control mRNA turnover and translation activities through association with trans‐acting RNA‐binding proteins that display high affinity for these AU‐rich regulatory elements. AU‐rich element RNA‐binding protein (AUF1), also known as heterogeneous nuclear ribonucleoprotein D (HNRNPD), is an extensively studied AU‐rich binding protein (AUBP). AUF1 has been shown to regulate ARE‐mRNA turnover, primarily functioning to promote rapid ARE‐mRNA degradation. In certain cellular contexts, AUF1 has also been shown to regulate gene expression at the translational and even the transcriptional level. AUF1 comprises a family of four related protein isoforms derived from a common pre‐mRNA by differential exon splicing. AUF1 isoforms have been shown to display multiple and distinct functions that include the ability to target ARE‐mRNA stability or decay, and transcriptional activation of certain genes that is controlled by their differential subcellular locations, expression levels, and post‐translational modifications. AUF1 has been implicated in controlling a variety of physiological functions through its ability to regulate the expression of numerous mRNAs containing 3′‐UTR AREs, thereby coordinating functionally related pathways. This review highlights the physiological functions of AUF1‐mediated regulation of mRNA and gene expression, and the consequences of deficient AUF1 levels in different physiological settings. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
       
  • MicroRNAs as therapeutic targets in human cancers
    • Abstract: MicroRNAs (miRNAs) are evolutionarily conserved, small, regulatory RNAs that negatively regulate gene expression. Extensive research in the last decade has implicated miRNAs as master regulators of cellular processes with essential role in cancer initiation, progression, and metastasis, making them promising therapeutic tools for cancer management. In this article, we will briefly review the structure, biogenesis, functions, and mechanism of action of these miRNAs, followed by a detailed analysis of the therapeutic potential of these miRNAs. We will focus on the strategies presently used for miRNA therapy; discuss their use and drawbacks; and the challenges and future directions for the development of miRNA‐based therapy for human cancers. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
       
  • The multifaceted roles of RNA binding in APOBEC cytidine deaminase
           functions
    • Abstract: Cytidine deaminases have important roles in the regulation of nucleoside/deoxynucleoside pools for DNA and RNA synthesis. The APOBEC family of cytidine deaminases (named after the first member of the family that was described, Apolipoprotein B mRNA Editing Catalytic Subunit 1, also known as APOBEC1 or A1) is a fascinating group of mutagenic proteins that use RNA and single‐stranded DNA (ssDNA) as substrates for their cytidine or deoxycytidine deaminase activities. APOBEC proteins and base‐modification nucleic acid editing have been the subject of numerous publications, reviews, and speculation. These proteins play diverse roles in host cell defense, protecting cells from invading genetic material, enabling the acquired immune response to antigens and changing protein expression at the level of the genetic code in mRNA or DNA. The amazing power these proteins have for interphase cell functions relies on structural and biochemical properties that are beginning to be understood. At the same time, the substrate selectivity of each member in the family and their regulation remains to be elucidated. This review of the APOBEC family will focus on an open question in regulation, namely what role the interactions of these proteins with RNA have in editing substrate recognition or allosteric regulation of DNA mutagenic and host‐defense activities. For further resources related to this article, please visit the WIREs website. Conflict of interest: KMP, RPB, and JDS are employees of OyaGen Inc, which is a drug development biotechnology company engaged in the therapeutic targeting of editing enzymes. Dr. Smith is the founder of OyaGen and, as a consultant, serves as CEO and CSO for OyaGen. Dr. Smith is a tenured full professor in the Department of Biochemistry and Biophysics, Center for RNA Biology and Cancer Center at the University of Rochester, School of Medicine and Dentistry in Rochester, NY.
       
  • Localization of mRNAs to the endoplasmic reticulum
    • Abstract: Almost all cells use mRNA localization to establish spatial control of protein synthesis. One of the best‐studied examples is the targeting and anchoring of mRNAs encoding secreted, organellar, and membrane‐bound proteins to the surface of the endoplasmic reticulum (ER). In this review, we provide a historical perspective on the research that elucidated the canonical protein‐mediated targeting of nascent‐chain ribosome mRNA complexes to the surface of the ER. We then discuss subsequent studies which provided concrete evidence that a subpopulation of mRNAs utilize a translation‐independent mechanism to localize to the surface of this organelle. This alternative mechanism operates alongside the signal recognition particle (SRP) mediated co‐translational targeting pathway to promote proper mRNA localization to the ER. Recent work has uncovered trans‐acting factors, such as the mRNA receptor p180, and cis‐acting elements, such as transmembrane domain coding regions, that are responsible for this alternative mRNA localization process. Furthermore, some unanticipated observations have raised the possibility that this alternative pathway may be conserved from bacteria to mammalian cells. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
       
  • Deadenylation: enzymes, regulation, and functional implications
    • Abstract: Lengths of the eukaryotic messenger RNA (mRNA) poly(A) tails are dynamically changed by the opposing effects of poly(A) polymerases and deadenylases. Modulating poly(A) tail length provides a highly regulated means to control almost every stage of mRNA lifecycle including transcription, processing, quality control, transport, translation, silence, and decay. The existence of diverse deadenylases with distinct properties highlights the importance of regulating poly(A) tail length in cellular functions. The deadenylation activity can be modulated by subcellular locations of the deadenylases, cis‐acting elements in the target mRNAs, trans‐acting RNA‐binding proteins, posttranslational modifications of deadenylase and associated factors, as well as transcriptional and posttranscriptional regulation of the deadenylase genes. Among these regulators, the physiological functions of deadenylases are largely dependent on the interactions with the trans‐acting RNA‐binding proteins, which recruit deadenylases to the target mRNAs. The task of these RNA‐binding proteins is to find and mark the target mRNAs based on their sequence features. Regulation of the regulators can switch on or switch off deadenylation and thereby destabilize or stabilize the targeted mRNAs, respectively. The distinct domain compositions and cofactors provide various deadenylases the structural basis for the recruitments by distinct RNA‐binding protein subsets to meet dissimilar cellular demands. The diverse deadenylases, the numerous types of regulators, and the reversible posttranslational modifications together make up a complicated network to precisely regulate intracellular mRNA homeostasis. This review will focus on the diverse regulators of various deadenylases and will discuss their functional implications, remaining problems, and future challenges. For further resources related to this article, please visit the WIREs website. Conflict of interest: The author has declared no conflicts of interest for this article.
       
  • Splicing factor mutations and cancer
    • Abstract: Recent advances in high‐throughput sequencing technologies have unexpectedly revealed that somatic mutations of splicing factor genes frequently occurred in several types of hematological malignancies, including myelodysplastic syndromes, other myeloid neoplasms, and chronic lymphocytic leukemia. Splicing factor mutations have also been reported in solid cancers such as breast and pancreatic cancers, uveal melanomas, and lung adenocarcinomas. These mutations were heterozygous and mainly affected U2AF1 (U2AF35), SRSF2 (SC35), SF3B1 (SF3B155 or SAP155), and ZRSR2 (URP), which are engaged in the initial steps of RNA splicing, including 3′ splice‐site recognition, and occur in a large mutually exclusive pattern, suggesting a common impact of these mutations on RNA splicing. In this study, splicing factor mutations in various types of cancers, their functional/biological effects, and their potential as therapeutic targets have been reviewed. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
       
  • Telomeric noncoding RNA: telomeric repeat‐containing RNA in telomere
           biology
    • Abstract: Telomeres are nucleoprotein structures that cap the ends of eukaryotic chromosomes, protecting them from degradation and activation of DNA damage response. For this reason, functional telomeres are vital to genome stability. For years, telomeres were assumed to be transcriptionally silent, because of their heterochromatic state. It was only recently shown that, in several organisms, telomeres are transcribed, giving rise to a long noncoding RNA (lncRNA) called telomeric repeat‐containing RNA (TERRA). Several lines of evidence now indicate that TERRA molecules play crucial roles in telomere homeostasis and telomere functions. Recent studies have shown that the expression and regulation of TERRA are dynamically controlled by each chromosome end. TERRA has been involved in the regulation of telomere length, telomerase activity, and heterochromatin formation at telomeres. The correct regulation of the telomeric transcripts may be essential to genome stability, and altered TERRA levels associate with tumorigenesis and cellular senescence. Thus, the study of the molecular mechanisms of TERRA biogenesis and function may advance the understanding of telomere‐related diseases, including cancer and aging. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
       
  • RNA biology and the adaptation of Cryptococcus neoformans to host
           temperature and stress
    • Abstract: Cryptococcus neoformans is an environmental fungus that can cause severe disease in humans. C. neoformans encounters a multitude of stresses within the human host to which it must adapt in order to survive and proliferate. Upon stressful changes in the external milieu, C. neoformans must reprogram its gene expression to properly respond to and combat stress in order to maintain homeostasis. Several studies have investigated the changes that occur in response to these stresses to begin to unravel the mechanisms of adaptation in this organism. Here, we review studies that have explored stress‐induced changes in gene expression with a focus on host temperature adaptation. We compare global messenger RNA (mRNA) expression data compiled from several studies and identify patterns that suggest that orchestrated, transient responses occur. We also utilize the available expression data to explore the possibility of a common stress response that may contribute to cellular protection against a variety of stresses in C. neoformans. In addition, we review studies that have revealed the significance of post‐transcriptional mechanisms of mRNA regulation in response to stress, and discuss how these processes may contribute to adaptation and virulence. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
       
  • Small RNAs in the Vibrionaceae: an ocean still to be explored
    • Abstract: In bacteria, the discovery of noncoding small RNAs (sRNAs) as modulators of gene expression in response to environmental signals has brought new insights into bacterial gene regulation, including control of pathogenicity. The Vibrionaceae constitute a family of marine bacteria of which many are responsible for infections affecting not only humans, such as Vibrio cholerae but also fish and marine invertebrates, representing the major cause of mortality in farmed marine species. They are able to colonize many habitats, existing as planktonic forms, in biofilms or associated with various hosts. This high adaptability is linked to their capacity to generate genetic diversity, in part through lateral gene transfer, but also by varying gene expression control. In the recent years, several major studies have illustrated the importance of small regulatory sRNAs in the Vibrionaceae for the control of pathogenicity and adaptation to environment and nutrient sources such as chitin, especially in V. cholerae and Vibrio harveyi. The existence of a complex regulatory network controlled by quorum sensing has been demonstrated in which sRNAs play central roles. This review covers major advances made in the discovery and elucidation of functions of Vibrionaceae sRNAs within the last 10 years. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
       
  • Understanding principles of miRNA target recognition and function through
           integrated biological and bioinformatics approaches
    • Abstract: In recent times, microRNA (miRNA) have emerged as primary regulators of fundamental biological processes including cellular differentiation, proliferation, apoptosis, as well as synaptic plasticity. However, miRNAs bind their targets with only partial complementarity, making it very challenging to determine exactly how a miRNA is functioning in specific biological environments. This review discusses key principles of miRNA target recognition and function which have emerged through the progressive advancement of biological and bioinformatics approaches. Ultimately, the integration of gene expression and biochemical methods with sequence‐ and systems‐based bioinformatics approaches will reveal profound insights regarding the importance of target contextual features in determining miRNA target recognition and regulatory outcome, as well as the importance of RNA interaction networks in enabling miRNA to regulate different target genes and functions in specific biological contexts. There is therefore a demand for the elegant design of future experiments such that principles of context‐specific miRNA target recognition and regulatory outcome can be accurately modeled in normal developmental and disease states. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
       
  • Translational reprogramming in cellular stress response
    • Abstract: Cell survival in changing environments requires appropriate regulation of gene expression, including translational control. Multiple stress signaling pathways converge on several key translation factors, such as eIF4F and eIF2, and rapidly modulate messenger RNA (mRNA) translation at both the initiation and the elongation stages. Repression of global protein synthesis is often accompanied with selective translation of mRNAs encoding proteins that are vital for cell survival and stress recovery. The past decade has seen significant progress in our understanding of translational reprogramming in part due to the development of technologies that allow the dissection of the interplay between mRNA elements and corresponding binding proteins. Recent genome‐wide studies using ribosome profiling have revealed unprecedented proteome complexity and flexibility through alternative translation, raising intriguing questions about stress‐induced translational reprogramming. Many surprises emerged from these studies, including wide‐spread alternative translation initiation, ribosome pausing during elongation, and reversible modification of mRNAs. Elucidation of the regulatory mechanisms underlying translational reprogramming will ultimately lead to the development of novel therapeutic strategies for human diseases. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
       
  • miRNA sponges: soaking up miRNAs for regulation of
           gene expression
    • Abstract: MicroRNAs (miRNAs) are small regulatory RNAs that act in an entangled web of interactions with target mRNAs to shape the cellular protein landscape by post‐transcriptional control of mRNA decay and translation. miRNAs are themselves subject to numerous regulatory mechanisms that adjust their prevalence and activity. Emerging evidence suggests that miRNAs are themselves targeted by regulatory RNA species, and the identification of several classes of noncoding RNA molecules carrying miRNA binding sites has added a new intricate dimension to miRNA regulation. Such miRNA ‘sponges’ bind miRNAs and competitively sequester them from their natural targets. Endogenous miRNA sponges, also termed competing endogenous RNAs (ceRNAs), act to buffer the activity of miRNAs on physiologically relevant targets. This class of sponges includes endogenously transcribed pseudogenes, long noncoding RNAs, and recently discovered circular RNAs and may act in large complex networks in conjunction with miRNAs to regulate the output of protein. With the growing demand of regulating miRNA activity for experimental purposes and potential future clinical use, naturally occurring miRNA sponges are providing inspiration for engineering of gene vector‐encoded sponges as potent inhibitors of miRNA activity. Combined with potent and versatile vector technologies, expression of custom‐designed sponges provides new means of managing miRNAs and soaking up miRNAs for therapeutic regulation of gene expression. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
       
  • Battle against RNA oxidation: molecular mechanisms for reducing oxidized
           RNA to protect cells
    • Abstract: Oxidation is probably the most common type of damage that occurs in cellular RNA. Oxidized RNA may be dysfunctional and is implicated in the pathogenesis of age‐related human diseases. Cellular mechanisms controlling oxidized RNA have begun to be revealed. Currently, a number of ribonucleases and RNA‐binding proteins have been shown to reduce oxidized RNA and to protect cells under oxidative stress. Although information about how these factors work is still very limited, we suggest several mechanisms that can be used to minimize oxidized RNA in various organisms. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
       
  • Genetic regulation of flowering time in annual and perennial plants
    • Abstract: Flowering time plays a significant role in the reproductive success of plants. So far, five major pathways to flowering have been characterized in Arabidopsis, including environmental induction through photoperiod, vernalization, and gibberellins and autonomous floral iation, and aging by sequentially operating miRNAs (typically miR156 and miR172) responding to endogenous cues. The balance of signals from these pathways is integrated by a common set of genes (FLOWERING LOCUS C, FLOWERING LOCUS T, LEAFY, and SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1) that determine the flowering time. Recent studies have indicated that epigenetic modification, alternative splicing, antisense RNA and chromatin silencing regulatory mechanisms play an important role in this process by regulating related flowering gene expression. In this review, we discuss the current understanding in genetic regulation of the phase transition from vegetative to reproductive growth by using Arabidopsis as a model. We also describe how this knowledge has been successfully applied for identifying homologous genes from perennial crops. Furthermore, detailed analysis of the similarities and differences between annual and perennial plants flowering will help elucidate the mechanisms of perennial plant maturation and regulation of floral initiation. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
       
 
 
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