Dokument: Deciphering principles of recognition of human immunodeficiency virus (HIV) splice sites
| Titel: | Deciphering principles of recognition of human immunodeficiency virus (HIV) splice sites | |||||||
| Weiterer Titel: | Entschlüsselung der Prinzipien zur Erkennung von Spleißstellen des Humanen Immundefizienz Virus (HIV) | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=37063 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20160203-145907-4 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | M.Sc. Peter, Jan Otto [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Schaal, Heiner [Gutachter] Prof. Dr. Willbold, Dieter [Gutachter] | |||||||
| Stichwörter: | HIV-1; pre-mRNA splicing; ESSV; hnRNP D | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 540 Chemie | |||||||
| Beschreibungen: | Ein Kennzeichen des Humanen Immundefizienz-Virus Typ 1 (HIV-1) ist die strikte Abhängigkeit der viralen Replikation vom alternativen Spleißen. Durch alternatives Spleißen entstehen aus der viralen prä-mRNA mehr als 40 verschiedene Spleißisoformen, die für wenigstens 18 virale Proteine kodieren. Um diese exprimieren zu können und eine effiziente virale Replikation zu ermöglichen, muss es eine fein ausgewogene Balance zwischen gespleißten und intronhaltigen mRNA-Isoformen geben. Die mutationsbasierte Inaktivierung des exonic splicing silencer V (ESSV) führt zu exzessivem Spleißen der HIV-1 prä-mRNA. Dadurch verschiebt sich die Balance zu gespleißten mRNA-Isoformen und verhindert somit die HIV-1 Replikation. Allerdings führte die Depletion des publizierten ESSV-Bindeproteins hnRNP A1, nicht wie angenommen, zu exzessivem Spleißen. Deshalb musste die Bindung eines anderen RNA-bindenden Proteins, welches die spleißinhibitorische Aktivität des ESSV aufrecht hält, angenommen werden. Im Rahmen dieser Doktorarbeit wurde gezeigt, dass hnRNP D, ein bekannter Regulator der mRNA-Stabilität und Erhaltung der Telomere, ebenfalls spezifisch an den ESSV binden kann. Weiterhin konnte nachgewiesen werden, dass die RNA-Bindung aller hnRNP D Isoformen die Erkennung von Spleißstellen beeinträchtigt und das Spleißen reprimiert. Zudem konnte durch Deletionsmutagenese demonstriert werden, dass in Abhängigkeit von der durch das Exon 7 kodierten Peptidsequenz hnRNP D auf zwei unterschiedliche Weisen das Spleißen der prä-mRNA inhibieren kann. Schließlich wurde gezeigt, dass eine exklusive hnRNP D Bindestelle anstelle des ESSV ebenfalls eine ausgewogene Balance zwischen gespleißter und intronhaltiger mRNA-Isoformen aufrechterhalten kann. Zusammengefasst konnte in dieser Doktorarbeit nachgewiesen werden, dass hnRNP D auch ein spleißregulatorisches Protein ist, das zusammen mit hnRNP A1 am ESSV das exzessive Spleißen der HIV-1 prä-mRNA unterbindet und somit zur effizienten HIV-1 Replikation beiträgt.One hallmark of Human Immunodeficiency Virus Type 1 (HIV-1) is the strict dependence of its viral replication on alternative splicing. Driven by alternative splicing more than 40 different transcript isoforms arise from the viral pre-mRNA, which encode at least 18 viral proteins. In order to express all viral proteins allowing efficient viral replication, a fragile balance between the intronless and intron-containing mRNAs has to be kept. Mutational inactivation of the exonic splicing silencer V (ESSV) was shown to result in excessive splicing of the HIV-1 pre-mRNA, shifting the balance towards intronless mRNA isoforms and thus inhibiting HIV-1 replication. However, depletion of the published ESSV binding protein hnRNP A1 did not as anticipated result in the onset of excessive splicing. Thus, binding of another RNA-binding protein could be supposed which sustains the splice inhibitory activity of the ESSV. In this thesis it was shown that hnRNP D, a known regulator of mRNA stability and telomere maintenance, specifically binds to the ESSV. Further, binding of each hnRNP D isoform to the RNA could be observed to interfere with the recognition of splice sites and thus to inhibit splicing. Moreover, deletion mutagenesis demonstrated that dependent on the peptide sequence encoded by alternative exon 7 hnRNP D mediated inhibition of pre-mRNA splicing occurs by two different mechanisms. Finally, an exclusive hnRNP D binding site replacing the ESSV was shown to maintain a viable balance of intronless to intron-containing mRNA isoforms. Altogether, hnRNP D represents a splicing regulatory protein that binds along with hnRNP A1 to the ESSV and thereby contributes to the regulation of HIV-1 pre-mRNA splicing, the prevention of excessive splicing and thus allows efficient viral replication. | |||||||
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| Lizenz: |  Urheberrechtsschutz | |||||||
| Bezug: | 10/09 bis 11/15 | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät » Institute » Institut für Virologie | |||||||
| Dokument erstellt am: | 03.02.2016 | |||||||
| Dateien geändert am: | 03.02.2016 | |||||||
| Datum der Promotion: | 10.11.2015 |
