Sui Generis Features of the First Intron
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Coupling of Spliceosome Complexity to Intron Diversity
bioRxiv preprint doi: https://doi.org/10.1101/2021.03.19.436190; this version posted March 20, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Coupling of spliceosome complexity to intron diversity Jade Sales-Lee1, Daniela S. Perry1, Bradley A. Bowser2, Jolene K. Diedrich3, Beiduo Rao1, Irene Beusch1, John R. Yates III3, Scott W. Roy4,6, and Hiten D. Madhani1,6,7 1Dept. of Biochemistry and Biophysics University of California – San Francisco San Francisco, CA 94158 2Dept. of Molecular and Cellular Biology University of California - Merced Merced, CA 95343 3Department of Molecular Medicine The Scripps Research Institute, La Jolla, CA 92037 4Dept. of Biology San Francisco State University San Francisco, CA 94132 5Chan-Zuckerberg Biohub San Francisco, CA 94158 6Corresponding authors: [email protected], [email protected] 7Lead Contact 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.03.19.436190; this version posted March 20, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. SUMMARY We determined that over 40 spliceosomal proteins are conserved between many fungal species and humans but were lost during the evolution of S. cerevisiae, an intron-poor yeast with unusually rigid splicing signals. We analyzed null mutations in a subset of these factors, most of which had not been investigated previously, in the intron-rich yeast Cryptococcus neoformans. -
Nuclear Expression of a Group II Intron Is Consistent with Spliceosomal Intron Ancestry
Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Nuclear expression of a group II intron is consistent with spliceosomal intron ancestry Venkata R. Chalamcharla, M. Joan Curcio, and Marlene Belfort1 Center for Medical Sciences, Wadsworth Center, New York State Department of Health, Albany, New York 12208, USA; and School of Public Health, State University of New York at Albany, Albany, New York 12201, USA Group II introns are self-splicing RNAs found in eubacteria, archaea, and eukaryotic organelles. They are mechanistically similar to the metazoan nuclear spliceosomal introns; therefore, group II introns have been invoked as the progenitors of the eukaryotic pre-mRNA introns. However, the ability of group II introns to function outside of the bacteria-derived organelles is debatable, since they are not found in the nuclear genomes of eukaryotes. Here, we show that the Lactococcus lactis Ll.LtrB group II intron splices accurately and efficiently from different pre-mRNAs in a eukaryote, Saccharomyces cerevisiae. However, a pre-mRNA harboring a group II intron is spliced predominantly in the cytoplasm and is subject to nonsense-mediated mRNA decay (NMD), and the mature mRNA from which the group II intron is spliced is poorly translated. In contrast, a pre-mRNA bearing the Tetrahymena group I intron or the yeast spliceosomal ACT1 intron at the same location is not subject to NMD, and the mature mRNA is translated efficiently. Thus, a group II intron can splice from a nuclear transcript, but RNA instability and translation defects would have favored intron loss or evolution into protein-dependent spliceosomal introns, consistent with the bacterial group II intron ancestry hypothesis. -
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. -
Sequences at the Exon-Intron Boundaries* (Split Gene/Mrna Splicing/Eukaryotic Gene Structure) R
Proc. Nati. Acad. Sci. USA Vol. 75, No. 10, pp. 4853-4857, October 1978 Biochemistry Ovalbumin gene: Evidence for a leader sequence in mRNA and DNA sequences at the exon-intron boundaries* (split gene/mRNA splicing/eukaryotic gene structure) R. BREATHNACH, C. BENOIST, K. O'HARE, F. GANNON, AND P. CHAMBON Laboratoire de Genetique Mol6culaire des Eucaryotes du Centre National de la Recherche Scientifique, Unite 44 de l'Institut National de la Sant6 et de la Recherche MWdicale, Institut de Chimie Biologique, Facult6 de Melecine, Strasbourg 67085, France Communicated by A. Frey-Wyssling, July 31, 1978 ABSTRACT Selected regions of cloned EcoRI fragments the 5' end of ov-mRNA and have revealed some interesting of the chicken ovalbumin gene have been sequenced. The po- features in the DNA sequences at exon-intron boundaries. sitions where the sequences coding for ovalbumin mRNA (ov- mRNA) are interrupted in the genome have been determined, and a previously unreported interruption in the DNA sequences MATERIALS AND METHODS coding for the 5' nontranslated region of the messenger has been discovered. Because directly repeated sequences are found at Plasmid pCR1 ov 2.1 containing the ov-ds-cDNA insert was exon-intron boundaries, the nucleotide sequence alone cannot prepared as described (9). EcoRI fragments "b," "c," and "d" define unique excision-ligation points for the processing of a previously cloned in X vectors (3) were transferred to the plas- possible ov-mRNA precursor. However, the sequences in these mid pBR 322. An EcoRI/HindIII of the EcoRI boundary regions share common features; this leads to the fragment proposal that there are, in fact, unique excision-ligation points fragment "a" containing the entirety of exon 7 (Fig. -
(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. -
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. -
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). -
The Lifespan of an MLL-Rearranged Therapy-Related Paediatric AML
Bone Marrow Transplantation (2015) 50, 1382–1384 © 2015 Macmillan Publishers Limited All rights reserved 0268-3369/15 www.nature.com/bmt LETTER TO THE EDITOR From initiation to eradication: the lifespan of an MLL-rearranged therapy-related paediatric AML Bone Marrow Transplantation (2015) 50, 1382–1384; doi:10.1038/ amplified by RT-PCR. DCP1A is predominantly cytoplasmic as part bmt.2015.155; published online 6 July 2015 of a protein complex involved in degradation of mRNAs.8 Upon stimulation by TGFB1 and interaction with SMAD4, it becomes nuclear contributing to the transactivation of TGF-α target genes.9 Therapy-related AML (tAML) is one of the most prevalent DCP1A is a novel MLL fusion partner in AML. The in vitro secondary malignant neoplasms in paediatric cancer survivors. transforming capacity of MLL-DCP1A was weaker than the more Estimates of incidence and association with causative chemo- common MLL-ENL fusion but it could nevertheless be clearly therapeutic agents are mainly based on epidemiological data. verified by colony formation in retroviral transduction-replating 10 Individual courses revealing the exact timing of the first clone assays (Figure 1d). appearance and its development under treatment are limited The cumulative sampling of bone marrow during preceding owing to the overall low incidence, which does not justify neuroblastoma treatment offered the unique possibility to repeated bone marrow sampling in order to detect the occurrence quantitatively backtrack the origin of the tAML by quantitative of potentially leukemic cells. real-time PCR using the genomic MLL-DCP1A breakpoint as a Here we report a unique case of tAML arising after neuro- molecular marker. -
Spliceosomal Intronogenesis
Spliceosomal intronogenesis Sujin Leea and Scott W. Stevensb,c,1 aGraduate Program in Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712; bDepartment of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712; and cInstitute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712 Edited by Jef D. Boeke, New York University School of Medicine, New York, NY, and approved April 20, 2016 (received for review March 30, 2016) The presence of intervening sequences, termed introns, is a defining it is clear that introns massively infiltrated the genome of the last characteristic of eukaryotic nuclear genomes. Once transcribed into eukaryotic common ancestor and that introns have continued to be pre-mRNA, these introns must be removed within the spliceosome gained and lost over evolutionary time (11, 18). before export of the processed mRNA to the cytoplasm, where it is Here we report the use of a reporter system designed to detect translated into protein. Although intron loss has been demonstrated events of intron gain and intron loss in the budding yeast Sac- experimentally, several mysteries remain regarding the origin and charomyces cerevisiae. With this reporter, we have captured, to our propagation of introns. Indeed, documented evidence of gain of an knowledge, the first verified examples of intron gain via intron intron has only been suggested by phylogenetic analyses. We report transposition in any eukaryote. the use of a strategy that detects selected intron gain and loss events. We have experimentally verified, to our knowledge, the first demon- Results strations of intron transposition in any organism. -
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. -
RNA Splicing: Unexpected Spliceosome Diversity Jan-Peter Kreivi and Angus I
View metadata, citation and similar papers at core.ac.uk brought to you by CORE 802 Dispatch provided by Elsevier - Publisher Connector RNA splicing: Unexpected spliceosome diversity Jan-Peter Kreivi and Angus I. Lamond A novel form of spliceosome, containing the minor Figure 1 snRNPs U11 and U12, splices a class of pre-mRNA introns with non-consensus splice sites. This unexpected GT–AG intron spliceosome diversity has interesting implications for the evolution and expression of eukaryotic genes. * AG GTRAGT TNCTRAC Py CAG G Address: Department of Biochemistry, University of Dundee, Dundee, 5' splice site Branch site 3' splice site DD1 4HN, Scotland, UK. Current Biology 1996, Vol 6 No 7:802–805 AT–AC intron © Current Biology Ltd ISSN 0960-9822 * ATATCCTT TCCTTAAC YCCAC The discovery that most protein-coding genes in eukary- 5' splice site Branch site 3' splice site otes are interrupted by one or more intervening sequences, or introns, was one of the major advances in © 1996 Current Biology molecular biology made in the 1970s [1,2]. The formation of mRNA thus involves a splicing process to remove Conserved elements in mammalian GT–AG and AT–AC introns. The introns from primary gene transcripts. Splicing takes first and last two nucleotides of the introns are shown in bold and the branch-site adenosine residue that forms the lariat structure is marked place in the nucleus before the mRNAs are exported to by an asterisk. The polypyrimidine tract that lies between the branch the cytoplasm for translation and occurs by a two-step site and 3′ intron–exon junction of GT–AG introns is lacking in AT–AC mechanism, in which both steps involve transesterifica- introns. -
Aspli: an Integrative R Package for Analysing Alternative Splicing Using RNA-Seq
ASpli: An integrative R package for analysing alternative splicing using RNA-seq Estefania Mancini, Andres Rabinovich, Javier Iserte, Marcelo Yanovsky, Ariel Chernomoretz May 19, 2021 Contents 1 Introduction ..............................2 2 Citation.................................2 3 Quick start ...............................3 4 Getting started ............................5 4.1 Installation ............................5 4.2 Required input data........................5 5 ASpli overview ............................6 6 Using ASpli ..............................7 6.1 binGenome: Binning the genome ..................8 6.1.1 Bin definition.......................9 6.1.2 Splicing event assignment..................9 6.2 Read counting .......................... 11 6.2.1 Targets data.frame definition................. 11 6.2.2 gbCounts: Summarize read overlaps against all feature levels.. 11 6.2.3 jCounts: Summarize junctions inclussion indices PSI, PIR and PJU........................... 13 6.3 Differential signals ........................ 16 6.3.1 gbDUreport: Bin-based coverage differential signals of AS.... 16 6.3.2 jDUreport: Junction-centered analysis of AS.......... 18 6.4 Integrative reports ........................ 20 6.4.1 splicingReport: bin and junction signals integration...... 20 6.4.2 integrateSignals(): Region specific summarization of differential usage signals........................ 20 6.4.3 exportSplicingReport: Export splicing reports in HTML pages... 24 6.4.4 exportIntegratedSignals(): Export integrated signals into HTML pages..........................