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Journal Cover   Wiley Interdisciplinary Reviews : RNA
  [SJR: 5.014]   [H-I: 21]   [1 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Online) 1757-7012
   Published by John Wiley and Sons Homepage  [1610 journals]
  • Structure and mechanism of the T‐box riboswitches
    • Authors: Jinwei Zhang; Adrian R. Ferré‐D'Amaré
      Abstract: In most Gram‐positive bacteria, including many clinically devastating pathogens from genera such as Bacillus, Clostridium, Listeria, and Staphylococcus, T‐box riboswitches sense and regulate intracellular availability of amino acids through a multipartite messenger RNA (mRNA)–transfer RNA (tRNA) interaction. The T‐box mRNA leaders respond to nutrient starvation by specifically binding cognate tRNAs and sensing whether the bound tRNA is aminoacylated, as a proxy for amino acid availability. Based on this readout, T‐boxes direct a transcriptional or translational switch to control the expression of downstream genes involved in various aspects of amino acid metabolism: biosynthesis, transport, aminoacylation, transamidation, and so forth. Two decades after its discovery, the structural and mechanistic underpinnings of the T‐box riboswitch were recently elucidated, producing a wealth of insights into how two structured RNAs can recognize each other with robust affinity and exquisite selectivity. The T‐box paradigm exemplifies how natural noncoding RNAs can interact not just through sequence complementarity but can add molecular specificity by precisely juxtaposing RNA structural motifs, exploiting inherently flexible elements and the biophysical properties of post‐transcriptional modifications, ultimately achieving a high degree of shape complementarity through mutually induced fit. The T‐box also provides a proof‐of‐principle that compact RNA domains can recognize minute chemical changes (such as tRNA aminoacylation) on another RNA. The unveiling of the structure and mechanism of the T‐box system thus expands our appreciation of the range of capabilities and modes of action of structured noncoding RNAs, and hints at the existence of networks of noncoding RNAs that communicate through both, structural and sequence specificity. 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.
      PubDate: 2015-05-08T15:46:56.484301-05:
      DOI: 10.1002/wrna.1285
  • Controlling translation via modulation of tRNA levels
    • Authors: Jeremy E. Wilusz
      Abstract: Transfer RNAs (tRNAs) are critical adaptor molecules that carry amino acids to a messenger RNA (mRNA) template during protein synthesis. Although tRNAs have commonly been viewed as abundant ‘house‐keeping’ RNAs, it is becoming increasingly clear that tRNA expression is tightly regulated. Depending on a cell's proliferative status, the pool of active tRNAs is rapidly changed, enabling distinct translational programs to be expressed in differentiated versus proliferating cells. Here, I highlight several post‐transcriptional regulatory mechanisms that allow the expression or functions of tRNAs to be altered. Modulating the modification status or structural stability of individual tRNAs can cause those specific tRNA transcripts to selectively accumulate or be degraded. Decay generally occurs via the rapid tRNA decay pathway or by the nuclear RNA surveillance machinery. In addition, the CCA‐adding enzyme plays a critical role in determining the fate of a tRNA. The post‐transcriptional addition of CCA to the 3′ ends of stable tRNAs generates the amino acid attachment site, whereas addition of CCACCA to unstable tRNAs prevents aminoacylation and marks the tRNA for degradation. In response to various stresses, tRNAs can accumulate in the nucleus or be further cleaved into small RNAs, some of which inhibit translation. By implementing these various post‐transcriptional control mechanisms, cells are able to fine‐tune tRNA levels to regulate subsets of mRNAs as well as overall translation rates. 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.
      PubDate: 2015-04-28T06:52:51.902812-05:
      DOI: 10.1002/wrna.1287
  • Computational Biology in microRNA
    • Authors: Yue Li; Zhaolei Zhang
      Abstract: MicroRNA (miRNA) is a class of small endogenous noncoding RNA species, which regulate gene expression post‐transcriptionally by forming imperfect base‐pair at the 3′ untranslated regions of the messenger RNAs. Since the 1993 discovery of the first miRNA let‐7 in worms, a vast number of studies have been dedicated to functionally characterizing miRNAs with a special emphasis on their roles in cancer. A single miRNA can potentially target ∼400 distinct genes, and there are over a 1000 distinct endogenous miRNAs in the human genome. Thus, miRNAs are likely involved in virtually all biological processes and pathways including carcinogenesis. However, functionally characterizing miRNAs hinges on the accurate identification of their mRNA targets, which has been a challenging problem due to imperfect base‐pairing and condition‐specific miRNA regulatory dynamics. In this review, we will survey the current state‐of‐the‐art computational methods to predict miRNA targets, which are divided into three main categories: (1) sequence‐based methods that primarily utilizes the canonical seed‐match model, evolutionary conservation, and binding energy; (2) expression‐based target prediction methods using the increasingly available miRNA and mRNA expression data measured for the same sample; and (3) network‐based method that aims identify miRNA regulatory modules, which reflect their synergism in conferring a global impact to the biological system of interest. We hope that the review will serve as a good reference to the new comers to the ever‐growing miRNA research field as well as veterans, who would appreciate the detailed review on the technicalities, strength, and limitations of each representative computational method. 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.
      PubDate: 2015-04-24T15:17:01.52854-05:0
      DOI: 10.1002/wrna.1286
  • Modulation of alternative splicing by anticancer drugs
    • Authors: Sayeed Ur Rehman; Mohammed Amir Husain, Tarique Sarwar, Hassan Mubarak Ishqi, Mohammad Tabish
      Abstract: Pre‐mRNA alternative splicing is a highly regulated process that generates multiple mRNAs coding different protein isoforms. These protein isoforms may have similar, different, or even opposing functions. Expression of genes involved in cell growth and apoptosis are often altered in cancer cells. Studying the alternative splicing patterns of these important genes can have a significant role in the treatment of cancer. Resistance to chemotherapy is often caused due to overexpression of anti‐apoptotic isoforms or suppression of pro‐apoptotic isoforms. Anticancer drugs are capable of modulating the expression of different transcript isoforms of genes. Some anticancer drugs induce pro‐apoptotic transcript isoforms leading to apoptosis or at least sensitizing cells to chemotherapy. However, in other cases, they shift the splicing toward isoforms having anti‐apoptotic functions thus conferring resistance to chemotherapy. This mini‐review summarizes the current knowledge about alternative splicing of some important genes involved in cancers. Furthermore, splicing patterns as well as generation of functionally distinct protein isoforms have also been mentioned. Role of various anticancer drugs in modulating alternative splicing of these genes has been reported along with a brief insight into their mechanism of action. Modulation of alternative splicing toward production of pro‐apoptotic isoforms of various genes by anticancer drugs offers great therapeutic potential in the treatment of cancer. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors declare that there is no conflict of interest in this article.
      PubDate: 2015-04-24T15:06:05.717225-05:
      DOI: 10.1002/wrna.1283
  • The role of LARP1 in translation and beyond
    • Authors: Jean‐Marc Deragon; Cécile Bousquet‐Antonelli
      Abstract: The LARP1 proteins form an evolutionarily homogeneous subgroup of the eukaryotic superfamily of La‐Motif (LAM) containing factors. Members of the LARP1 family are found in most protists, fungi, plants, and animals. We review here evidence suggesting that LARP1 are key versatile messenger RNA (mRNA)‐binding proteins involved in regulating important biological processes such as gametogenesis, embryogenesis, sex determination, and cell division in animals, as well as acclimation to stress in yeasts and plants. LARP1 proteins perform all these essential tasks likely by binding to key mRNAs and regulating their stability and/or translation. In human, the impact of LARP1 over cell division and proliferation is potentially under the control of the TORC1 complex. We review data suggesting that LARP1 is a direct target of this master signaling hub. TOR‐dependent LARP1 phosphorylation could specifically enhance the translation of TOP mRNAs providing a way to promote translation, growth, and proliferation. Consequently, LARP1 is found to be significantly upregulated in many malignant cell types. In plants, LARP1 was found to act as a cofactor of the heat‐induced mRNA degradation process, an essential acclimation strategy leading to the degradation of more than 4500 mRNAs coding for growth and development housekeeping functions. In Saccharomyces cerevisiae, the LARP1 proteins (Slf1p and Sro9p) are important, among other things, for copper resistance and oxidative stress survival. LARP1 proteins are therefore emerging as critical ancient mRNA‐binding factors that evolved common as well as specific targets and regulatory functions in all eukaryotic lineages. 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.
      PubDate: 2015-04-17T18:50:39.153834-05:
      DOI: 10.1002/wrna.1282
  • The emerging landscape of small nucleolar RNAs in cell biology
    • Authors: Fabien Dupuis‐Sandoval; Mikaël Poirier, Michelle S. Scott
      Abstract: Small nucleolar RNAs (snoRNAs) are a large class of small noncoding RNAs present in all eukaryotes sequenced thus far. As a family, they have been well characterized as playing a central role in ribosome biogenesis, guiding either the sequence‐specific chemical modification of pre‐rRNA (ribosomal RNA) or its processing. However, in higher eukaryotes, numerous orphan snoRNAs were described over a decade ago, with no known target or ascribed function, suggesting the possibility of alternative cellular functionality. In recent years, thanks in great part to advances in sequencing methodologies, we have seen many examples of the diversity that exists in the snoRNA family on multiple levels. In this review, we discuss the identification of novel snoRNA members, of unexpected binding partners, as well as the clarification and extension of the snoRNA target space and the characterization of diverse new noncanonical functions, painting a new and extended picture of the snoRNA landscape. Under the deluge of novel features and functions that have recently come to light, snoRNAs emerge as a central, dynamic, and highly versatile group of small regulatory RNAs. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors declare no conflict of interest for this article.
      PubDate: 2015-04-16T04:12:21.721286-05:
      DOI: 10.1002/wrna.1284
  • PSF: nuclear busy‐body or nuclear facilitator'
    • Authors: Christopher A. Yarosh; Joseph R. Iacona, Carol S. Lutz, Kristen W. Lynch
      Abstract: PTB‐associated splicing factor (PSF) is an abundant and essential nucleic acid‐binding protein that participates in a wide range of gene regulatory processes and cellular response pathways. At the protein level, PSF consists of multiple domains, many of which remain poorly characterized. Although grouped in a family with the proteins p54nrb/NONO and PSPC1 based on sequence homology, PSF contains additional protein sequence not included in other family members. Consistently, PSF has also been implicated in functions not ascribed to p54nrb/NONO or PSPC1. Here, we provide a review of the cellular activities in which PSF has been implicated and what is known regarding the mechanisms by which PSF functions in each case. We propose that the complex domain arrangement of PSF allows for its diversity of function and integration of activities. Finally, we discuss recent evidence that individual activities of PSF can be regulated independently from one another through the activity of domain‐specific co‐factors. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors declare no conflict of interest.
      PubDate: 2015-04-01T11:26:45.424986-05:
      DOI: 10.1002/wrna.1280
  • Issue information
  • Post‐transcriptional regulation in corticogenesis: how
           RNA‐binding proteins help build the brain
    • Abstract: The cerebral cortex, the brain structure responsible for our higher cognitive functions, is built during embryonic development in a process called corticogenesis. During corticogenesis, neural stem cells generate distinct populations of progenitors and excitatory neurons. These new neurons migrate radially in the cortex, eventually forming neuronal layers and establishing synaptic connections with other neurons both within and outside the cortex. Perturbations to corticogenesis can result in severe neurodevelopmental disorders, thus emphasizing the need to better understand molecular regulation of brain development. Recent studies in both model organisms and humans have collectively highlighted roles for post‐transcriptional regulation in virtually all steps of corticogenesis. Genomic approaches have revealed global RNA changes associated with spatial and temporal regulation of cortical development. Additionally, genetic studies have uncovered RNA‐binding proteins (RBPs) critical for cell proliferation, differentiation, and migration within the developing neocortex. Many of these same RBPs play causal roles in neurodevelopmental pathologies. In the developing neocortex, RBPs influence diverse steps of mRNA metabolism, including splicing, stability, translation, and localization. With the advent of new technologies, researchers have begun to uncover key transcripts regulated by these RBPs. Given the complexity of the developing mammalian cortex, a major challenge for the future will be to understand how dynamic RNA regulation occurs within heterogeneous cell populations, across space and time. In sum, post‐transcriptional regulation has emerged as a critical mechanism for driving corticogenesis and exciting direction of future research. 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.
  • Recombinant messenger RNA technology and its application in cancer
           immunotherapy, transcript replacement therapies, pluripotent stem cell
           induction, and beyond
    • Abstract: In recent years, the interest in using messenger RNA (mRNA) as a therapeutic means to tackle different diseases has enormously increased. This holds true not only for numerous preclinical studies, but mRNA has also entered the clinic to fight cancer. The advantages of using mRNA compared to DNA were recognized very early on, e.g., the lack of risk for genomic integration, or the expression of the encoded protein in the cytoplasm without the need to cross the nuclear membrane. However, it was generally assumed that mRNA is just not stable enough to give rise to sufficient expression of the encoded protein. Yet, an initially small group of mRNA aficionados could demonstrate that the stability of mRNA and the efficiency, by which the encoded protein is translated, can be significantly increased by selecting the right set of cis‐acting structural elements (including the 5′‐cap, 5′‐ and 3′‐untranslated regions, poly(A)‐tail, and modified building blocks). In parallel, significant advances in RNA packaging and delivery have been made, extending the potential for this molecule. This paved the way for further work to prove mRNA as a promising therapeutic for multiple diseases. Here, we review the developments to optimize mRNA regarding stability, translational efficiency, and immune‐modulating properties to enhance its functionality and efficacy as a therapeutic. Furthermore, we summarize the current status of preclinical and clinical studies that use mRNA for cancer immunotherapy, for the expression of functional proteins as so‐called transcript (or protein) replacement therapy, as well as for induction of pluripotent stem cells. For further resources related to this article, please visit the WIREs website. Conflict of interest: All authors are employees of BioNTech RNA Pharmaceuticals GmbH, a company that develops mRNA‐based therapeutics. In addition, ANK, FE, MAP, and US are inventors on patent applications, which cover distinct aspects of using mRNA as a therapeutic.
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