DOCSLIB.ORG

A Tale of Two Tails

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Tale of Two Tails news and views ity for a series of different orientations in the assumes that there are no intrinsic places in Nigel W. Daw is in the Department of same animal allowed Bonhoeffer and Grin- the cortex that would attract the formation Ophthalmology and Visual Science, Yale University vald6 (using intrinsic signals of activity from of pinwheels. This has been suggested as a School of Medicine, 330 Cedar Street, New Haven, upper layers of cortex7) to show that the factor in positioning of the blobs for colour Connecticut 06520-8061, USA. pinwheel model is correct. in the macaque visual cortex10. e-mail: [email protected] There are many models of how the cortex Wolf and Geisel have used mathematical 1. Wolf, F. & Geisel, T. Nature 395, 73–78 (1998). develops to achieve this pattern8. Cats and approaches that are common in physics but 2. Mountcastle, V. B. J. Neurophysiol. 20, 408–434 (1957). 3. Hubel, D. H. & Wiesel, T. N. J. Physiol. (Lond.) 160, 106–154 macaques show a pattern of orientation rare in biology. In turbulent flow, for exam- (1962). selectivity as soon as the eyes open shortly ple, aspects of a system’s behaviour can be 4. Hubel, D. H. & Wiesel, T. N. J. Comp. Neurol. 158, 267–294 after (or at) birth. But ferrets, which are born predicted from basic symmetries without (1974). 5. Braitenberg, V. & Braitenberg, C. Biol. Cybern. 33, 179–188 8 at an earlier stage of development, show little knowing the detailed nature of the interac- (1979). orientation selectivity when their eyes open. tions between components of the system. 6. Bonhoeffer, T. & Grinvald, A. Nature 353, 429–431 (1991). Instead, orientation selectivity develops to Because the nervous system is made up of 7. Grinvald, A., Lieke, E. E., Frostig, R. D., Gilbert, C. D. & Wiesel, T. N. Nature 324, 361–364 (1986). adult levels during the fifth and sixth weeks billions of cells and trillions of synapses, with 8. Erwin, E., Obermayer, K. & Schulten, K. Neural Comp. 7, after birth, under the influence of nerve-cell detailed interactions that are unknowable 425–468 (1995). activity9. in practice, mathematical approaches may 9. Chapman, B., Stryker, M. P. & Bonhoeffer, T. J. Neurosci. 16, 1 6443–6453 (1996). Wolf and Geisel now suggest that all have a future in predicting the overall behav- 10.Kuljis, R. O. & Rakic, P. Proc. Natl Acad. Sci. USA 87, 5303–5306 models for the development of orientation iour of the system. (1990). selectivity are subject to symmetry princi- ples. The authors first assume that columns RNA processing with a similar orientation preference tend to be a particular distance apart. Their second A tale of two tails assumption is that patterns resulting from (i) David Bentley shifting the pattern parallel to the cortical surface; (ii) rotating the pattern parallel to the cortical surface; and (iii) shifting all ori- he fate of RNAs in the nucleus is deter- sequence YSPTSPS, found at the carboxy entation preferences by the same angle, will mined by the polymerase that made terminus of the pol II large subunit — are arise with the same probability. Their final them. For example, the same primary not efficiently capped, spliced or cleaved at T 4,5 assumption is that the pattern arises from transcript that will give rise to a messenger the poly(A) site . This suggests that the many random factors, and that Gaussian RNA if made by RNA polymerase II (pol II), CTD helps to target mRNA processing fac- statistics apply. Their mathematics then will never mature if is made by pol I, pol III tors to pol II transcripts6,7. Hirose and Man- shows that the expected density of pin- or a bacteriophage RNA polymerase1,2. How ley have now discovered that the CTD facili- wheels is given by can we explain this link between the tates the 38 RNA cleavage reaction, even in ρ = π(1+α) machines that make and process mRNAs? the absence of transcription. They suggest 3 8 L2 On page 93 of this issue, Hirose and Manley that, in effect, the CTD is a cofactor for 3 bring us one step closer to an answer. They processing. where L is the average spacing of columns, report that the carboxy-terminal domain Production of a mature mRNA 38 end and a is a number that describes the struc- (CTD) — a protein domain unique to pol II can be reconstituted in vitro with cleavage/ ture of spatial correlations. One therefore — acts as part of the protein complex that polyadenylation specificity factor (CPSF), expects to find at least p pinwheels in an area fashions the 38 end of the mature mRNA by cleavage-stimulation factor (CstF), cleav- of size L2. cleavage and polyadenylation. age factors CFI and CFII, and poly(A)poly- In fact, the density of pinwheels varies The formation of 38 ends is a two-step merase (PAP)8. The association of CPSF from 3.75 in an area of size L2 in macaque, to process in which the RNA transcript is and CstF with the CTD in vitro4, and the 2.1–2.6 in tree shrew, with intermediate val- cleaved downstream of the sequence colocalization of CstF and phosphorylated ues for squirrel monkey, ferret and cat. Thus, AAUAAA, then a poly(A) tail is added at the pol II in vivo (Fig. 1), indicate that a stable either there is some process that prevents cut end. RNAs made in vivo by pol II lacking ‘mRNA factory’ complex of pol II with pro- development from being carried to comple- the CTD — a conserved repeat of the cessing factors carries out synthesis and tion in the cat and tree shrew, where the value is substantially below p, or the density of Figure 1 Colocalization of the pinwheels develops to a value greater than p, cleavage-stimulation factor then decreases through annihilation of pin- CstF and phosphorylated RNA wheels. Wolf and Geisel propose that such an polymerase II (pol II). annihilation could occur through melding Immunofluorescence of of a pair of pinwheels — one with clockwise Drosophila polytene chirality and another with anticlockwise chromosomes with anti-pol II chirality. monoclonal antibody (left) The annihilation of pinwheels is an and rabbit antibody against intriguing possibility. But it is not supported Suppressor of forked, the by the few observations available, which Drosophila homologue of CstF show a series of orientation maps that does (right). (Courtesy of M. Sikes not change much with age8. Areas with and A. Beyer, University of longer stretches of parallel slabs — which are Virginia.) predicted to arise when two pinwheels merge — do not seem to appear much more fre- quently in the older patterns. So, Wolf and Geisel’s predictions still need to be rigorous- ly tested. Moreover, the mathematics NATURE | VOL 395 | 3 SEPTEMBER 1998 21 Nature © Macmillan Publishers Ltd 1998 news and views Figure 2 Model for activation of Daedalus 38 processing by the pol II PAP carboxy-terminal domain Zero-tolerance policing Pol II (CTD). Hirose and Manley3 have CPSF shown that the CTD is part of Millions of potentially lethal cell Pol II the protein complex that carries mutations occur in each of us every day. P out cleavage and We notice nothing; the immune system - C CstF D TD- polyadenylation to produce a arrests and executes the offenders T P C CPSF mature messenger RNA instantly. But with advancing age, its CF II AAUAAA CstFG/U 5' transcript. CPSF, vigilance slackens. Mutations start to go 8 CF II CF I cleavage/polyadenylation unchecked; and we succumb to the CF I PAP specificity factor; CstF, cleavage- melancholy neoplastic or degenerative 5' AAUAAA G/U stimulation factor; CFI, cleavage diseases of old age. factor I; CFII, cleavage factor II; So Daedalus is extending his scheme of PAP, poly(A)polymerase. last week for priming the immune system against all normal biological proteins. He maturation of the primary transcript9. to this model, which is more consistent with now wants to prime it against abnormal Hirose and Manley provide an insight the effect of creatine phosphate, the CTD proteins as well — in particular, the into how the mRNA factory operates. They behaves as a cofactor or allosteric activator. abnormal ones expressed on the surfaces followed up the curious observation that, in One possible target for allosteric activation is of malfunctioning human cells. a purified system, cleavage at the poly(A) site CstF, which binds the CTD in vitro4. The DREADCO volunteers are now providing is stimulated by creatine phosphate and by importance of this interaction for scaffold- small biopsy tissue samples of blood, lung, phosphoamino acids. They reasoned that ing or allosteric activation could be tested gut, and so on, to be cultured in the usual these compounds may mimic a phospho- using CTD mutants that do not bind CstF. way. The cultures will then be attacked protein that allosterically activates the cleav- It is now clear that pol II stimulates 38 with mutagens, ultraviolet light, X-rays, age reaction. An attractive candidate phos- processing, both in vivo and in vitro, through and such, to induce as many mutations in phoprotein is pol II — the CTD undergoes a the CTD. Conversely, poly(A) factors may them as possible. The battered and cycle of hyperphosphorylation and dephos- affect pol II by influencing the decision to misfiring cells will express all sorts of crazy phorylation (mainly at residues two and five terminate or elongate the RNA chain. Termi- and altered proteins on their surfaces. of the YSPTSPS repeat10) as pol II cycles nation depends on transcription of the These will be extracted, and injected back through transcriptional initiation, elonga- poly(A) signal11, poly(A) factors12 and the into the volunteer from whom the cells tion and termination.
Load more

Recommended publications
  • News & Views Research
    NEWS & VIEWS RESEARCH may exhibit some tissue specificity in humans. Upstream intron Downstream intron a Sibley et al. found that genes with long introns sequence sequence tend to be expressed in the human nervous Precursor RNA system, and they identified recursively spliced 3' Splice 5' Splice RNAs expressed in the human brain6. Duff site site First step et al. detected some selectivity for recursive splicing in the brain in a screen of 20 human tissues (including fetal brain and adult cerebel- Second step lum), but this may partly reflect the difficulty of detecting recursively spliced RNAs in tis- Mature mRNA sues that express such RNAs at low levels. It will be important to determine whether this b RS exon specificity, if real, results from the tendency of recursively spliced genes to be expressed in the brain, or whether cells in the nervous system have factors that promote recursive Competing 5' splice sites First step splicing. Many genes that have long introns, including those that undergo recursive splicing, are linked to neurological diseases and to Second step 9–11 Second step autism . Whether these conditions are sometimes triggered by errors in the multi- step recursive RNA-splicing process will be an exciting avenue for future studies. ■ NMD Heidi Cook-Andersen and Miles F. Wilkinson are in the Department of Reproductive Medicine, University of Figure 1 | Mechanisms of recursive splicing. a, In recursive splicing, long intron sequences of precursor California, San Diego, La Jolla, California, RNA are removed in a stepwise process mediated by juxtaposed internal 3ʹ and 5ʹ splice sites. In the first step, 92093, USA.
    [Show full text]
  • (Bsc Zoology and Microbiology) Concept of Introns and Exons
    Unit-5 Molecular Biology (BSc Zoology and Microbiology) Concept of introns and exons Most of the portion of a gene in higher eukaryotes consists of noncoding DNA that interrupts the relatively short segments of coding DNA. The coding sequences are called exons. The noncoding sequences are called introns. Intron: An intron is a portion of a gene that does not code for amino acids An intron is any nucleotide sequence within a gene which is represented in the primary transcript of the gene, but not present in the final processed form. In other words, Introns are noncoding regions of an RNA transcript which are eliminated by splicing before translation. Sequences that are joined together in the final mature RNA after RNA splicing are exons. Introns are very large chunks of RNA within a messenger RNA molecule that interfere with the code of the exons. And these introns get removed from the RNA molecule to leave a string of exons attached to each other so that the appropriate amino acids can be encoded for. Introns are rare in genes of prokaryotes. #Look carefully at the diagram above, we have already discussed about the modification and processing of eukaryotic RNA. In which 5’ guanine cap and 3’poly A tail is added. So at that time, noncoding regions i.e. introns are removed. We hv done ths already. Ok Exon: The coding sequences are called Exon. An exon is the portion of a gene that codes for amino acids. In the cells of plants and animals, most gene sequences are broken up by one or more DNA sequences called introns.
    [Show full text]
  • Current Perspectives in Intronic Micro Rnas (Mirnas)
    Journal of Biomedical Science (2006) 13:5–15 5 DOI 10.1007/s11373-005-9036-8 Current perspectives in intronic micro RNAs (miRNAs) Shao-Yao Ying & Shi-Lung Lin Department of Cell & Neurobiology, Keck School of Medicine, BMT-403, University of Southern California, 1333 San Pablo Street, Los Angeles, CA, 90033, USA Received 27 May 2005; accepted 14 September 2005 Ó 2005 National Science Council, Taipei Key words: fine-tuning of gene function, functional/structural genomics, gene expression, genetic regula- tion, intronic microRNA, miRNA biogenesis, miRNA, post-translational modification, regulatory gene Summary MicroRNAs (miRNAs), small single-stranded regulatory RNAs capable of interfering with intracellular messenger RNAs (mRNAs) that contain either complete or partial complementarity, are useful for the design of new therapies against cancer polymorphism and viral mutation. Numerous miRNAs have been reported to induce RNA interference (RNAi), a post-transcriptional gene silencing mechanism. Intronic miRNAs, derived from introns by RNA splicing and Dicer processing, can interfere with intracellular mRNAs to silence that gene expression. The intronic miRNAs differ uniquely from previously described intergenic miRNAs in the requirement of type II RNA polymerases (Pol-II) and spliceosomal components for its biogenesis. Several kinds of intronic miRNAs have been identified in Caenorhabditis elegans, mouse and human cells; however, neither their function nor application has been reported. To this day, the computer searching program for miRNA seldom include the intronic portion of protein-coding RNAs. The functional significance of artificially generated intronic miRNAs has been successfully ascertained in several biological systems such as zebrafishes, chicken embryos and adult mice, indicating the evolutionary pres- ervation of this gene regulation system in vivo.
    [Show full text]
  • RNA Splice Sites Classification Using Convolutional Neural Network Models
    RNA Splice Sites Classification Using Convolutional Neural Network Models Thanyathorn Thanapattheerakul Worrawat Engchuan Daniele Merico School of Information Technology, The Centre for Applied Genomics, Molecular Diagnostics, King Mongkut’s University of Genetics and Genome Biology, The Deep Genomics, Technology Thonburi, Hospital for Sick Children, Toronto, Ontario, Canada Bangkok, Thailand Toronto, Ontario, Canada [email protected] [email protected] [email protected] Narumol Doungpan Kiyota Hashimoto Jonathan H. Chan Faculty of Engineering, Faculty of Technology and School of Information Technology, King Mongkut’s University of Environment, King Mongkut’s University of Technology Thonburi, Prince of Songkla University, Technology Thonburi, Bangkok, Thailand Phuket, Thailand Bangkok, Thailand [email protected] [email protected] [email protected] Abstract—RNA splicing refers to the elimination of non- completely make it loss of function. The alternative splicing coding region on transcribed pre-messenger ribonucleic acid can produce different functional proteins, which could lead (RNA). Identifying splicing site is an essential step which can to causing abnormal states in human [3]. be used to gain novel insights of alternative splicing as well as Many studies have proposed models to recognize the splicing defects, potentially cause malfunction of protein splice sites to reveal which splice sites contain a mutation resulting from mutations at splice site. In this work, we that may cause a splicing error. One common method to propose a data preprocessing step applying to RNA sequences recognize binding sites in motif sequences is called Position- and the models leveraging Convolutional Neural Network (CNN). The preprocessing step includes reducing sequence Weight-Matrix (PWM).
    [Show full text]
  • The CTD Role in Cotranscriptional RNA Processing and Surveillance
    CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector FEBS Letters 582 (2008) 1971–1976 Minireview The CTD role in cotranscriptional RNA processing and surveillance Se´rgio F. de Almeida, Maria Carmo-Fonseca* Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal Received 4 April 2008; revised 13 April 2008; accepted 14 April 2008 Available online 22 April 2008 Edited by Ulrike Kutay proteins specific to each snRNP. The selection of specific splice Abstract In higher eukaryotes, the production of mature mes- senger RNA that exits the nucleus to be translated into protein sites (ss) on a particular pre-mRNA substrate relies on an intri- requires precise and extensive processing of the nascent tran- cate interplay involving the cooperative binding of trans-acting script. The processing steps include 50-end capping, splicing, splicing proteins to cis-acting sequence elements in the pre- and 30-end formation. Pre-mRNA processing is coupled to tran- mRNA. In mammals, an intron is defined by four short and scription by mechanisms that are not well understood but involve poorly conserved consensus sequences: the exon–intron junc- the carboxyl-terminal domain (CTD) of the largest subunit of tions (50ss and 30ss); the branch point sequence; and the poly- RNA polymerase II. This review focuses on recent findings that pyrimidine tract (Table 1). These sequences are recognized by provide novel insight into the role of the CTD in promoting RNA base pairing with the spliceosomal snRNAs (Fig. 1). In addi- processing and surveillance. tion, both exons and introns contain weak binding sites for a Ó 2008 Federation of European Biochemical Societies.
    [Show full text]
  • Glossary of Terms Note: Words in Bold in a Definition Indicate Terms Also Defined in This Glossary
    Glossary of Terms Note: Words in bold in a definition indicate terms also defined in this Glossary Term Definition “3 prime”; Refers to carbon 3 of the nucleic acid sugar component (either ribose in RNA or deoxyribose in DNA) to which additional nucleotides may be added by 3' polymerase, often used to refer to that end of a single-stranded DNA or RNA molecule where the 3' carbon retains its hydroxyl group (-OH) and no further nucleotides are bonded. “5 prime”; Refers to carbon 5 of the nucleic acid sugar component (either ribose in RNA or deoxyribose in DNA), to which the triphosphate is attached in a nucleotide 5' triphosphate, often used to refer to that end of a single-stranded DNA or RNA molecule where the 5' carbon's phosphate group(s) is/are unattached to a preceding nucleotide. The inclusion or exclusion of certain exons in the splicing reactions that determine the sequences included in the final mRNA product. This mechanism is utilized to generate a series of closely related protein isoforms, which differ by the inclusion alternative splicing or exclusion of the particular protein regions encoded by those exons. Alternative splicing is directed by RNA-binding proteins that may block, or stimulate, utilization of a particular splice site. The basic building block of proteins, a small molecule with a -C-C- core, an amine group (-NH2) at one end and a carboxylic acid group (-COOH) at the other end. The amino acid general structure can be represented as NH2-CHR-COOH, where R can be any of 20 different functional groups of acidic, basic, or nonpolar character.
    [Show full text]
  • Protein-Synthesis.Pdf
    Protein Synthesis Contents Introduction ........................................................................................................................ 1 DNA Transcription ............................................................................................................... 1 The Primary Transcript ........................................................................................................ 4 Translation .......................................................................................................................... 7 Protein Structure............................................................................................................... 11 References ........................................................................................................................ 11 Resources .......................................................................................................................... 11 Introduction The genetic message carried on the DNA molecule is a code. This code is ultimately translated into a sequence of amino acids that, when complete, becomes a protein. Proteins carry out the “business” of the cell. Some proteins are used as structural components of cells, some are used to transport other molecules, still others are charged with directing chemical reactions. The latter class of proteins is the enzymes. Regardless of the role played by a protein in the cell one aspect is the same, they are all encoded in the base sequences of DNA. The path from DNA sequence to protein
    [Show full text]
  • The Chloroplast Trans-Splicing RNA–Protein Supercomplex from the Green Alga Chlamydomonas Reinhardtii
    cells Review The Chloroplast Trans-Splicing RNA–Protein Supercomplex from the Green Alga Chlamydomonas reinhardtii Ulrich Kück * and Olga Schmitt Allgemeine und Molekulare Botanik, Faculty for Biology and Biotechnology, Ruhr-Universität Bochum, Universitätsstraße 150, 44780 Bochum, Germany; [email protected] * Correspondence: [email protected]; Tel.: +49-234-32-28951 Abstract: In eukaryotes, RNA trans-splicing is a significant RNA modification process for the end-to- end ligation of exons from separately transcribed primary transcripts to generate mature mRNA. So far, three different categories of RNA trans-splicing have been found in organisms within a diverse range. Here, we review trans-splicing of discontinuous group II introns, which occurs in chloroplasts and mitochondria of lower eukaryotes and plants. We discuss the origin of intronic sequences and the evolutionary relationship between chloroplast ribonucleoprotein complexes and the nuclear spliceosome. Finally, we focus on the ribonucleoprotein supercomplex involved in trans-splicing of chloroplast group II introns from the green alga Chlamydomonas reinhardtii. This complex has been well characterized genetically and biochemically, resulting in a detailed picture of the chloroplast ribonucleoprotein supercomplex. This information contributes substantially to our understanding of the function of RNA-processing machineries and might provide a blueprint for other splicing complexes involved in trans- as well as cis-splicing of organellar intron RNAs. Keywords: group II intron; trans-splicing; ribonucleoprotein complex; chloroplast; Chlamydomonas reinhardtii Citation: Kück, U.; Schmitt, O. The Chloroplast Trans-Splicing RNA–Protein Supercomplex from the Green Alga Chlamydomonas reinhardtii. 1. Introduction Cells 2021, 10, 290. https://doi.org/ One of the unexpected and outstanding discoveries in 20th century biology was the 10.3390/cells10020290 identification of discontinuous eukaryotic genes [1,2].
    [Show full text]
  • Alternatively Spliced Genes
    1 Alternatively Spliced Genes Jane Y. Wu1,2,LiyaYuan1 and Necat Havlioglu1 1Washington University School of Medicine, St. Louis, MO, USA 2John F. Kennedy Center for Research on Human Development, Vanderbilt University Medical Center, Nashville, TN, USA 1 Pre-mRNA Splicing and Splicing Machinery 3 1.1 Splicing Machinery: Spliceosome 3 1.2 Splicing Signals 4 1.3 Spliceosomal UsnRNP Biogenesis 12 1.4 Spliceosome Assembly 13 1.5 Biochemical Mechanisms of pre-mRNA Splicing 17 2 Alternative pre-mRNA Splicing 17 2.1 Alternative Splicing and its Role in Regulating Gene Activities and Generating Genetic Diversity 17 2.1.1 Different Patterns of Alternative Splicing 17 2.1.2 Alternative Splicing and Genetic Diversity 18 2.2 Mechanisms Underlying Alternative Splicing Regulation 19 2.2.1 Splicing Signals and Splicing Regulatory Elements 20 2.2.2 Trans-acting Splicing Regulators 23 2.3 Tissue-specific and Developmentally Regulated Alternative Splicing 26 2.4 Regulation of Alternative Splicing in Response to Extracellular Stimuli 27 3 Pre-mRNA Splicing and Human Diseases 28 3.1 Splicing Defects in Human Diseases 28 3.2 Molecular Mechanisms Underlying Splicing Defects Associated with Disease 33 4 Perspectives on Diagnosis and Treatment of Diseases Caused by pre-mRNA Splicing Defects 36 4.1 Diagnosis of Human Diseases Caused by Splicing Defects 36 2 Alternatively Spliced Genes 4.2 Potential Therapeutic Approaches 37 4.2.1 Oligonucleotide-based Approaches: Antisense, RNAi, and Chimeric Molecules 37 4.2.2 Ribozymes 37 4.2.3 SMaRT 38 4.2.4 Chemical Compounds 38 5 Concluding Remarks 38 Acknowledgment 39 Bibliography 39 Books and Reviews 39 Keywords Pre-mRNA Nascent transcripts that are precursors of mature messenger RNAs.
    [Show full text]
  • Spliceosomal Pre-Mrna Splicing Methods and Protocols M ETHODS in MOLECULAR BIOLOGY
    Methods in Molecular Biology 1126 Klemens J. Hertel Editor Spliceosomal Pre-mRNA Splicing Methods and Protocols M ETHODS IN MOLECULAR BIOLOGY Series Editor John M. Walker School of Life Sciences University of Hertfordshire Hat fi eld, Hertfordshire, AL10 9AB, UK For further volumes: http://www.springer.com/series/7651 Spliceosomal Pre-mRNA Splicing Methods and Protocols Edited by Klemens J. Hertel Department of Microbiology & Molecular Genetics, University of California, Irvine, CA, USA Editor Klemens J. Hertel Department of Microbiology & Molecular Genetics University of California Irvine , CA , USA ISSN 1064-3745 ISSN 1940-6029 (electronic) ISBN 978-1-62703-979-6 ISBN 978-1-62703-980-2 (eBook) DOI 10.1007/978-1-62703-980-2 Springer New York Heidelberg Dordrecht London Library of Congress Control Number: 2014931088 © Springer Science+Business Media, LLC 2014 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifi cally for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher’s location, in its current version, and permission for use must always be obtained from Springer.
    [Show full text]
  • Post-Transcriptional Modification by / Hanaa Shawky Ragheb Supervised by Prof.Dr / Rasha El Tahan Course / Molecular Biology
    Post-transcriptional modification By / Hanaa Shawky Ragheb Supervised by prof.dr / Rasha El Tahan Course / Molecular Biology Molecular biology: is a branch of science concerning biological activity at the molecular level. The field of molecular biology overlaps with biology and chemistry and in particular, genetics and biochemistry. A key area of molecular biology concerns understanding how various cellular systems interact in terms of the way DNA, RNA and protein synthesis function. Molecular biology looks at the molecular mechanisms behind processes such as replication, transcription, translation and cell function. One way to describe the basis of molecular biology is to say it concerns understanding how genes are transcribed into RNA and how RNA is then translated into protein. However, this simplified picture is currently be reconsidered and revised due to new discoveries concerning the roles of RNA. Central Dogma (Gene Expression): The central dogma of molecular biology explains that the information flow for genes is from the DNA genetic code to an intermediate RNA copy and then to the proteins synthesized from the code. The key ideas underlying the dogma were first proposed by British molecular biologist Francis Crick in 1958. Replication : DNA replication The formation of new and, hopefully, identical copies of complete genomes. DNA replication occurs every time a cell divides to form two daughter cells. Under the influence of enzymes, DNA unwinds and the two strands separate over short lengths to form numerous replication forks, each of which is called a replicon. The separated strands are temporarily sealed with protein to prevent re-attachment. A short RNA sequence called a primer is formed for each strand at the fork.
    [Show full text]
  • RNA-Targeting Splicing Modifiers: Drug Development and Screening Assays
    molecules Review RNA-Targeting Splicing Modifiers: Drug Development and Screening Assays Zhichao Tang, Junxing Zhao , Zach J. Pearson, Zarko V. Boskovic and Jingxin Wang * Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66047, USA; [email protected] (Z.T.); [email protected] (J.Z.); [email protected] (Z.J.P.); [email protected] (Z.V.B.) * Correspondence: [email protected] Abstract: RNA splicing is an essential step in producing mature messenger RNA (mRNA) and other RNA species. Harnessing RNA splicing modifiers as a new pharmacological modality is promising for the treatment of diseases caused by aberrant splicing. This drug modality can be used for infectious diseases by disrupting the splicing of essential pathogenic genes. Several antisense oligonucleotide splicing modifiers were approved by the U.S. Food and Drug Administration (FDA) for the treatment of spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD). Recently, a small-molecule splicing modifier, risdiplam, was also approved for the treatment of SMA, highlighting small molecules as important warheads in the arsenal for regulating RNA splicing. The cellular targets of these approved drugs are all mRNA precursors (pre-mRNAs) in human cells. The development of novel RNA-targeting splicing modifiers can not only expand the scope of drug targets to include many previously considered “undruggable” genes but also enrich the chemical-genetic toolbox for basic biomedical research. In this review, we summarized known Citation: Tang, Z.; Zhao, J.; Pearson, splicing modifiers, screening methods for novel splicing modifiers, and the chemical space occupied Z.J.; Boskovic, Z.V.; Wang, J. by the small-molecule splicing modifiers.
    [Show full text]