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Analysis of the in Vivo Functions and Assembly Pathway of Small Subunit Ribosomal Proteins in Saccharomyces Cerevisiae

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Analysis of the in Vivo Functions and Assembly Pathway of Small Subunit Ribosomal Proteins in Saccharomyces Cerevisiae Analysis of the in vivo functions and assembly pathway of small subunit ribosomal proteins in Saccharomyces cerevisiae DISSERTATION ZUR ERLANGUNG DES DOKTORGRADES DER NATURWISSENSCHAFTEN (DR. RER. NAT.) DER NATURWISSENSCHAFTLICHEN FAKULTÄT III – BIOLOGIE UND VORKLINISCHE MEDIZIN DER UNIVERSITÄT REGENSBURG vorgelegt von Sébastien Ferreira-Cerca aus Rochefort s/Mer, Frankreich Regensburg, November 2007 Promotionsgesuch eingereicht am: 14 November 2007 Die Arbeit wurde angeleitet von: Prof. Dr. Herbert Tschochner und Prof. Dr. Pierre- Emmanuel Gleizes. Prüfungausschuss: Vorsitzender: Prof. Dr. Gernot Längst 1. Gutachter: Prof. Dr. Herbert Tschochner 2. Gutachter: Prof. Dr. Pierre-Emmanuel Gleizes 3. Prüfer: Prof. Dr. Thomas Dresselhaus Tag der mündlichen Prüfung: 15 Februar 2008 Diese Arbeit wurde von Oktober 2003 bis November 2007 unter der Anleitung von Dr.!Philipp Milkereit, Prof. Dr. Herbert Tschochner (Universität Regensburg, Deutschland) und Prof. Dr. Pierre-Emmanuel Gleizes (Université Toulouse, Frankreich) am Lehrstuhl für Biochemie III des Instituts für Biochemie, Genetik und Mikrobiologie der Universität Regensburg angefertigt. Ich erkläre hiermit, dass ich diese Dissertation selbst verfasst und keine anderen als die angegebenen Quellen und Hilfsmittel verwendet haben. Diese Arbeit war bisher noch nicht Bestandteil eines Prüfungsverfahrens, andere Promotionsversuche wurden nicht unternommen. Regensburg, 25 Februar 2008 À la mémoire de mon père, TABLE OF CONTENTS i TABLE OF CONTENTS SUMMARY - RÉSUMÉ - ZUSAMMENFASSUNG................................................................................................ 1 INTRODUCTION......................................................................................................................................................... 5 1. THE RIBOSOME: STRUCTURE AND FUNCTION. ....................................................................... 5 1.1. A BRIEF HISTORY OF PROTEIN SYNTHESIS RESEARCH................................................................................. 5 1.2. THE RIBOSOME: STRUCTURE AND COMPOSITION........................................................................................ 7 1.3. RIBOSOME FUNCTION. ............................................................................................................................... 13 2. RIBOSOMES BIOGENESIS AND ASSEMBLY. ............................................................................. 18 2.1. RIBOSOME COMPONENTS: GENOMIC ORGANISATION AND SYNTHESIS..................................................... 18 2.2. MATURATION OF RIBOSOMAL RNA.......................................................................................................... 22 2.3. TRANSIENT INTERACTIONS OF RIBOSOME BIOGENESIS FACTORS WITH PRE-RIBOSOMES AND THEIR FUNCTION IN EUKARYOTIC RIBOSOME BIOGENESIS.................................................................................. 40 3. FUNCTIONS OF RIBOSOMAL PROTEINS.................................................................................... 52 3.1. CONTRIBUTION OF R-PROTEINS TO RIBOSOME BIOGENESIS...................................................................... 52 3.2. CONTRIBUTION OF R-PROTEINS TO RIBOSOME FUNCTION. ....................................................................... 66 3.3. EXTRA-RIBOSOMAL FUNCTION OF R-PROTEINS. ....................................................................................... 68 4. AIMS OF THIS WORK: IN VIVO FUNCTIONS AND ASSEMBLY PATHWAY OF SSU R–PROTEINS IN EUKARYOTES...................................................................................................... 70 RESULTS ................................................................................................................................................................... 71 1. FUNCTION OF SSU R-PROTEINS IN RIBOSOME BIOGENESIS............................................ 71 1.1. MOST OF THE SSU R-PROTEINS ARE REQUIRED FOR YEAST CELL GROWTH............................................. 71 1.2. MOST OF THE SSU R-PROTEINS ARE REQUIRED FOR SYNTHESIS OF MATURE 18S RRNA....................... 75 1.3. SSU R-PROTEINS ARE REQUIRED AT DIFFERENT STEPS OF THE SSU BIOGENESIS.................................... 77 1.4. A SUBSET OF SSU R-PROTEINS IS REQUIRED FOR EFFICIENT PRE-40S SUBUNIT EXPORT........................ 81 1.5. SUMMARY ON THE FUNCTION OF SSU R-PROTEINS IN RIBOSOME BIOGENESIS........................................ 85 2. IN VIVO ASSEMBLY PATHWAY OF SSU R-PROTEINS............................................................ 87 2.1. A COLLECTION OF TAGGED SSU R-PROTEINS TO STUDY IN VIVO ASSEMBLY OF SSU R-PROTEINS......... 87 2.2. IN VIVO ASSEMBLY OF EUKARYOTIC SSU R-PROTEINS WITH PRE-40S SUBUNITS.................................... 88 2.3. IN VIVO ASSEMBLY OF EUKARYOTIC SSU R-PROTEINS WITH RRNA PRECURSORS AFTER DEPLETION OF RPS5........................................................................................................................................................... 93 2.4. ASSEMBLY OF EUKARYOTIC SSU R-PROTEINS WITH 20S PRE-RRNA AFTER IN VIVO DEPLETION OF RPS15......................................................................................................................................................... 96 2.5. IN VIVO ASSEMBLY STATUS OF NASCENT NUCLEAR SSU AFTER INACTIVATION OF THE RIBOSOME EXPORTIN CRM1P. ..................................................................................................................................... 97 2.6. SUMMARY ON THE IN VIVO ASSEMBLY PATHWAY OF SSU R-PROTEINS. .................................................. 99 3. FUNCTION OF SSU R-PROTEINS IN TRANSLATION............................................................. 101 3.1. ARE SOME ESSENTIAL SSU R-PROTEINS INVOLVED IN PROTEIN TRANSLATION?................................... 101 3.2. ARE THE KNOWN NON-ESSENTIAL SSU R-PROTEINS INVOLVED IN PROTEIN TRANSLATION? ............... 102 4. RELATIVE STOICHIOMETRY OF SSU R-PROTEINS............................................................. 105 TABLE OF CONTENTS ii DISCUSSION & PERSPECTIVES........................................................................................................................ 107 1. R-PROTEINS AND SSU BIOGENESIS........................................................................................... 107 1.1. R-PROTEIN ASSEMBLY AND PRE-18S RRNA MATURATION/ TRANSPORT ARE INTERCONNECTED........ 107 1.2. COMPARISON BETWEEN PRO- AND EUKARYOTIC SSU R-PROTEIN FUNCTIONS...................................... 113 1.3. THE MULTIPLE FUNCTIONS OF R-PROTEINS IN RIBOSOME BIOGENESIS................................................... 116 1.4. ON THE IMPORTANCE OF CO-TRANSCRIPTIONAL ASSEMBLY OF R-PROTEINS......................................... 117 1.5. R-PROTEIN ASSEMBLY AND RRNA MODIFICATIONS: A CONNECTION?.................................................. 118 1.6. LOCALISATION OF EUKARYOTIC SSU R-PROTEINS IN THE RIBOSOME STRUCTURE. .............................. 120 2. R-PROTEINS AND TRANSLATION............................................................................................... 122 2.1. R-PROTEINS AS MODULATOR OF RIBOSOME FUNCTION. ......................................................................... 122 2.2. THE RIBOSOME AS A REGULATOR OF GENE EXPRESSION: “THE RIBOSOME FILTER HYPOTHESIS”. ........ 122 3. CONCLUSION: SSU R-PROTEINS IN VIVO FUNCTIONS AND ASSEMBLY PATHWAY. ................................................................................................................................................................. 125 MATERIALS & METHODS .................................................................................................................................. 127 1. MICROBIOLOGY WORK. ............................................................................................................... 127 1.1. WORK WITH ESCHERICHIA COLI............................................................................................................... 127 1.2. WORK WITH SACCHAROMYCES CEREVISIAE.............................................................................................. 128 2. WORK WITH NUCLEIC ACIDS..................................................................................................... 134 2.1. WORK WITH DNA.................................................................................................................................... 134 2.2. WORK WITH RNA.................................................................................................................................... 136 3. WORK WITH PROTEINS................................................................................................................. 142 3.1. DETERMINATION OF PROTEIN CONCENTRATION..................................................................................... 142 3.2. EXTRACTION OF PROTEINS. ..................................................................................................................... 142 3.3. SDS-POLYACRYLAMIDE GEL ELECTROPHORESIS (SDS-PAGE). ........................................................... 142 3.4. WESTERN BLOTTING. .............................................................................................................................. 143 3.5. IMMUNOBLOTTING AND DETECTION. ...................................................................................................... 143 4. ADDITIONAL BIOCHEMICAL METHODS................................................................................
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