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Regulation of Alternative Splice Site Selection by Reversible Protein Phosphorylation

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Regulation of Alternative Splice Site Selection by Reversible Protein Phosphorylation Regulation of alternative splice site selection by reversible protein phosphorylation Den Naturwissenschaftlichen Fakultäten der Friedrich-Alexander-Universität Erlangen-Nürnberg zur Erlangung des Doktorgrades vorgelegt von Tatyana Novoyatleva aus Baku, Aserbaidschan 2006 Als Dissertation genehmigt von den Naturwissenschaftlichen Fakultäten der Universität Erlangen-Nürnberg. Tag der mündlichen Prüfung: 21 Dezember 2006 Vorsitzender der Prüfungskomission: Prof. Dr. Eberhard Bänsch Erstberichterstatter: PD Dr. Fritz Titgemeyer Zweitberichterstatter: Prof. Dr. Michael Wegner To my parents ACKNOWLEDGMENTS The work presented here was performed in the Institute of Biochemistry at Friedrich- Alexander-University Erlangen-Nürnberg and was supported by the Families of Spinal Muscular Atrophy. I would like to thank Prof. Dr. Stefan Stamm for giving me the opportunity to work in his lab and for his strong motivated support and kind guidance during my Ph.D. research. I acknowledge my past and current colleagues, who became good friends during my graduation: Nataliya Benderskaya, Bettina Heinrich, Shivendra Kishore, Dominique Olbert, Zhaiyi Zhang, Yesheng Tang for their help and for creating a good atmosphere in the group. Also I would like to thank previous lab members: Annette Hartmann, Oliver Stoss, Peter Stoilov, Marieta Gencheva and Ilona Rafalska for their advise. I would like to thank Prof. Mathieu Bollen for his scientific remarks and for providing the opportunity for fruitful collaborations during my Ph.D research. I would like to thank Laurent Bracco and Pascale Fehlbaum for performing CHIP splicearray analysis. I would like to thank Dr. Matthew Buthcbach and Prof. Arthur Burges for performing experiments on transgenic mice. I would like to thank Prof. Michael Wegner and his group for sharing their resources with us. Many thanks to my friends for their encouragement and support throughout my time here in Erlangen: Larisa Ivashina, Kseniya Kashkevich, Tatiana Cheusova. Special thanks go to all my friends from home. I am very grateful to my sister for giving me strength and a comfortable atmosphere at home. My sincere thanks go to my dear husband who was always with me, in all good and bad moments, staying my best friend. Спасибо ВАМ мои родные мама и папа за все что для меня сделали. PUBLICATIONS Novoyatleva, T., Heinrich, B., Tang, Y., Benderska, N., Ben-Dov, C., Bracco, L., Bollen, M. and Stamm, S. Protein phosphatase 1 binds to the RNA recognition motif of several splicing factors and regulates alternative pre-mRNA processing (submitted). Novoyatleva, T., Rafalska, I., Tang, Y. and Stamm, S. (2006). Pre-mRNA missplicing as a cause of human disease. Prog. Mol. Subcell. Biol., 44, 27-46. Novoyatleva, T. and Stamm, S. (2005). Friedrich-Alexander-Universität European Patent Erlangen-Nürnberg, Protein phosphatase 1 regulates the usage of Tra2-beta1 dependent alternative exons. Use of PP-1 inhibitors to prevent missplicing events. EP# 05 013659.7. Stoss, O.,1 Novoyatleva, T.,1 Gencheva, M., Olbrich, M., Benderska, N. and Stamm, S. (2004). p59fyn mediated phosphorylation regulates the activity of the tissue-specific splicing factor rSLM-1. Mol. Cell. Neurosci., 27, 8-21. (1-equal contribution to the manuscript). Heinrich, B., Zhang, Z., Novoyatleva, T. and Stamm, S. Aberrant pre-mRNA splicing as a cause of human disease (2005). Journal of Clinical Ligand Assay, 7, 68-74. Tang, Y., Novoyatleva, T., Benderska, N., Kishore, S., Thanaraj, T.A., Stamm, S. (2004). Analysis of alternative splicing in vivo using minigenes. Handbook of RNA Biochemistry, WILEY-VCH Verlag GmbH & Co. KHaA, Weinheim. Contents CONTENTS CONTENTS....................................................................................................... I TABLE OF FIGURES AND TABLES ................................................................... IV ABBREVIATIONS ..........................................................................................VII ZUSAMMENFASSUNG .......................................................................................X ABSTRACT ....................................................................................................XII 1. INTRODUCTION...........................................................................................1 1.1. CONSTITUTIVE SPLICING AND THE BASAL SPLICING MACHINERY .....................................2 1.1.2. Mode of alternative splicing...............................................................3 1.1.3. Spliceosome commitment .................................................................3 1.1.4. Action of splicing factors ...................................................................5 1.1.5. The SR and SR-related family of proteins ............................................6 1.1.6. Role of SR and SR related proteins in constitutive and alternative splicing7 1.1.7. hnRNPs ..........................................................................................9 1.1.8. Human Transformer-2 beta .............................................................10 1.1.9. SLM-1 and SLM-2 are Sam68 like mammalian proteins ....................... 12 1.1.10. Coupling of splicing and transcription..............................................14 1.2. PHOSPHORYLATION DEPENDENT CONTROL OF THE PRE-MRNA SPLICING MACHINERY............ 15 1.2.1. Protein Phosphatase 1 ....................................................................16 1.2.2. Combinatorial control of PP1c ..........................................................19 1.2.3. Regulation of PP1 by diverse mechanisms .........................................19 1.3. ALTERNATIVE SPLICING AND HUMAN DISEASE........................................................24 1.3.1. Human diseases that are caused by mutation in splicing signals ...........24 1.3.2. Mutation of cis-acting elements .......................................................25 1.3.3. Spinal muscular atrophy (SMA)........................................................27 1.3.4. Current Cellular Models for Evaluating SMA Therapeutics..................... 28 1.3.5. Changes of trans-factors associated with diseases .............................. 30 1.3.6. Treatment of diseases caused by missplicing .....................................31 1.3.6.1. Gene Transfer Methods............................................................................31 1.3.6.2. Low molecular weight drugs.....................................................................32 1.3.7. Diagnostics ...................................................................................32 1.4. MECHANISM OF SPLICING...............................................................................32 2. RESEARCH OVERVIEW...............................................................................36 3. MATERIALS AND METHODS .......................................................................37 3.1. MATERIALS ...............................................................................................37 3.1.1. Chemicals.....................................................................................37 3.1.2. Enzymes ......................................................................................38 3.1.3. Cell lines and media .......................................................................38 3.1.4. Preparation of LB media .................................................................39 3.1.5. Bacterial strains and media .............................................................39 3.1.6. Antibiotics ....................................................................................39 3.1.7. Antibodies ....................................................................................40 3.1.8. Plasmids.......................................................................................40 3.1.9. Primers ........................................................................................42 3.2. METHODS ................................................................................................44 3.2.1. Amplification of DNA by PCR............................................................44 3.2.2. Plasmid DNA isolation (“mini-prep” method) ......................................45 3.2.3. Determination of nucleic acids concentration .....................................46 3.2.4. Electrophoresis of DNA ...................................................................46 3.2.5. Elution of DNA from agarose gels .....................................................46 3.2.6. Site-directed mutagenesis of DNA ....................................................46 i Contents 3.2.7. Preparation of competent E.coli cells ................................................ 47 3.2.8. Transformation of E.coli cells...........................................................48 3.2.9. Expression and purification of GST-tagged proteins in bacteria .............48 3.2.10. Expression and purification of HIS-tagged proteins in Baculovirus Expression System..................................................................................49 3.2.11. Determination of protein concentration ........................................... 52 3.2.12. Dephosphorylation assay of HIS Tra2-beta1 recombinant protein........52 3.2.13. In vitro transcription / translation of DNA into radiolabelled protein and GST pull-down assay ...............................................................................53 3.2.14. Freezing, thawing and subculturing of eukaryotic cells....................... 53 3.2.15. Subculturing of primary
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