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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  [1607 journals]
  • Cutting, dicing, healing and sealing: the molecular surgery of tRNA
    • Authors: Raphael R.S. Lopes; Alan C. Kessler, Carla Polycarpo, Juan D. Alfonzo
      Abstract: All organisms encode transfer RNAs (tRNAs) that are synthesized as precursor molecules bearing extra sequences at their 5′ and 3′ ends; some tRNAs also contain introns, which are removed by splicing. Despite commonality in what the ultimate goal is (i.e., producing a mature tRNA), mechanistically, tRNA splicing differs between Bacteria and Archaea or Eukarya. The number and position of tRNA introns varies between organisms and even between different tRNAs within the same organism, suggesting a degree of plasticity in both the evolution and persistence of modern tRNA splicing systems. Here we will review recent findings that not only highlight nuances in splicing pathways but also provide potential reasons for the maintenance of introns in tRNA. Recently, connections between defects in the components of the tRNA splicing machinery and medically relevant phenotypes in humans have been reported. These differences will be discussed in terms of the importance of splicing for tRNA function and in a broader context on how tRNA splicing defects can often have unpredictable consequences. 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: 2015-03-06T10:23:38.974748-05:
      DOI: 10.1002/wrna.1279
  • Kinetics effects and modeling of mRNA turnover
    • Authors: Maria Concetta Palumbo; Lorenzo Farina, Paola Paci
      Abstract: Broader comprehension of gene expression regulatory mechanisms can be gained from a global analysis of how transcription and degradation are coordinated to orchestrate complex cell responses. The role of messenger RNA (mRNA) turnover modulation in gene expression levels has become increasingly recognized. From such perspective, in this review we briefly illustrate how a simple but effective mathematical model of mRNA turnover and some experimental findings, may together shed light on the molecular mechanisms underpinning the major role of mRNA decay rates in shaping the kinetics of gene activation and repression. 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: 2015-03-01T21:48:52.562072-05:
      DOI: 10.1002/wrna.1277
  • Dissecting the roles of TRBP and PACT in double‐stranded RNA
           recognition and processing of noncoding RNAs
    • Authors: Alex Heyam; Dimitris Lagos, Michael Plevin
      Abstract: HIV TAR RNA‐binding protein (TRBP) and Protein Activator of PKR (PACT) are double‐stranded (ds) RNA‐binding proteins that participate in both small regulatory RNA biogenesis and the response to viral dsRNA. Despite considerable progress toward understanding the structure–function relationship of TRBP and PACT, their specific roles in these seemingly distinct cellular pathways remain unclear. Both proteins are composed of three copies of the double‐stranded RNA‐binding domain, two of which interact with dsRNA, while the C‐terminal copy mediates protein–protein interactions. PACT and TRBP are found in a complex with the endonuclease Dicer and facilitate processing of immature microRNAs. Their precise contribution to the Dicing step has not yet been defined: possibilities include precursor recruitment, rearrangement of dsRNA within the complex, loading the processed microRNA into the RNA‐induced silencing complex, and distinguishing different classes of small dsRNA. TRBP and PACT also interact with the viral dsRNA sensors retinoic acid‐inducible gene I (RIG‐I) and double‐stranded RNA‐activated protein kinase (PKR). Current models suggest that PACT enables RIG‐I to detect a wider range of viral dsRNAs, while TRBP and PACT exert opposing regulatory effects on PKR. Here, the evidence that implicates TRBP and PACT in regulatory RNA processing and viral dsRNA sensing is reviewed and discussed in the context of their molecular structure. The broader implications of a link between microRNA biogenesis and the innate antiviral response pathway are also considered. 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: 2015-01-28T07:11:41.725874-05:
      DOI: 10.1002/wrna.1272
  • Functional roles of alternative splicing factors in human disease
    • Authors: Benjamin Cieply; Russ P. Carstens
      Abstract: Alternative splicing (AS) is an important mechanism used to generate greater transcriptomic and proteomic diversity from a finite genome. Nearly all human gene transcripts are alternatively spliced and can produce protein isoforms with divergent and even antagonistic properties that impact cell functions. Many AS events are tightly regulated in a cell‐type or tissue‐specific manner, and at different developmental stages. AS is regulated by RNA‐binding proteins, including cell‐ or tissue‐specific splicing factors. In the past few years, technological advances have defined genome‐wide programs of AS regulated by increasing numbers of splicing factors. These splicing regulatory networks (SRNs) consist of transcripts that encode proteins that function in coordinated and related processes that impact the development and phenotypes of different cell types. As such, it is increasingly recognized that disruption of normal programs of splicing regulated by different splicing factors can lead to human diseases. We will summarize examples of diseases in which altered expression or function of splicing regulatory proteins has been implicated in human disease pathophysiology. As the role of AS continues to be unveiled in human disease and disease risk, it is hoped that further investigations into the functions of numerous splicing factors and their regulated targets will enable the development of novel therapies that are directed at specific AS events as well as the biological pathways they impact. 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: 2015-01-28T07:08:19.081555-05:
      DOI: 10.1002/wrna.1276
  • Computational challenges, tools, and resources for analyzing co‐ and
           post‐transcriptional events in high throughput
    • Authors: Emad Bahrami‐Samani; Dat T. Vo, Patricia Rosa de Araujo, Christine Vogel, Andrew D. Smith, Luiz O. F. Penalva, Philip J. Uren
      Abstract: Co‐ and post‐transcriptional regulation of gene expression is complex and multifaceted, spanning the complete RNA lifecycle from genesis to decay. High‐throughput profiling of the constituent events and processes is achieved through a range of technologies that continue to expand and evolve. Fully leveraging the resulting data is nontrivial, and requires the use of computational methods and tools carefully crafted for specific data sources and often intended to probe particular biological processes. Drawing upon databases of information pre‐compiled by other researchers can further elevate analyses. Within this review, we describe the major co‐ and post‐transcriptional events in the RNA lifecycle that are amenable to high‐throughput profiling. We place specific emphasis on the analysis of the resulting data, in particular the computational tools and resources available, as well as looking toward future challenges that remain to be addressed. 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: 2014-12-16T08:41:34.011111-05:
      DOI: 10.1002/wrna.1274
  • Structure and mechanism of the T‐box riboswitches
    • 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.
  • Modulation of alternative splicing by anticancer drugs
    • 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.
  • Computational Biology in microRNA
    • 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.
  • Controlling translation via modulation of tRNA levels
    • 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.
  • The emerging landscape of small nucleolar RNAs in cell biology
    • 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.
  • The role of LARP1 in translation and beyond
    • 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.
  • Issue information
  • PSF: nuclear busy‐body or nuclear facilitator'
    • 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.
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