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Lavoie Mathieu Phd 2015.Pdf Université de Sherbrooke Étude des mécanismes de dégradation sélective de l’ARN par la RNase III de Saccharomyces cerevisiae Par Mathieu Lavoie Département de microbiologie et infectiologie Thèse présentée à la Faculté de médecine et des sciences de la santé en vue de l’obtention du grade de philosophiae doctor (Ph.D.) en microbiologie Thèse déposée le 7 janvier 2015 à Sherbrooke, Québec, Canada Membres du jury d’évaluation Pr Brendan Bell, département de microbiologie et infectiologie Pr Sherif Abou Elela, département de microbiologie et infectiologie Pr Luc Gaudreau, département de biologie, Université de Sherbrooke Pr Marvin Wickens, Departement of Biochemistry, University of Wisconsin-Madison Étude des mécanismes de dégradation sélective de l’ARN par la RNase III de Saccharomyces cerevisiae Par Mathieu Lavoie Département de microbiologie et d’infectiologie Thèse présentée à la Faculté de médecine et des sciences de la santé en vue de l’obtention du grade de philosophiae doctor (Ph.D.) en microbiologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, Canada, J1H 5N4 RÉSUMÉ Chez toutes les cellules, une modulation précise de l’expression des gènes est essentielle afin de réguler adéquatement leur métabolisme et de s’adapter aux changements environnementaux. En effet, c’est l’expression des gènes, plutôt que la séquence d’ADN, qui détermine en grande partie la diversité et la complexité des organismes. Celle-ci dépend principalement des changements dans les niveaux d’ARNs cellulaires résultant de la modification de l’équilibre entre leurs taux relatifs de synthèse et de dégradation. Alors que la régulation transcriptionnelle a été largement étudiée par le passé, des études récentes révèlent que la stabilité de l’ARN joue aussi un rôle important dans le modelage du transcriptome. Toutefois, les mécanismes qui assurent la dégradation précise et sélective des ARNs sont globalement mal compris. Au cours de cette thèse, j’ai utilisé la ribonucléase III de levure Saccharomyces cerevisiae (Rnt1p) comme modèle pour étudier comment des transcrits spécifiques sont ciblés pour la dégradation et évaluer sa contribution à la régulation de l’expression génique. Les résultats indiquent que Rnt1p régule l’expression des gènes en utilisant une spécificité élargie pour des structures tige- boucles d’ARN. En effet, un nouveau motif structurel de Rnt1p permet la discrimination des tige-boucles ayant une séquence spécifique tout en bloquant la liaison à des hélices génériques d’ARN double-brin. D’un autre côté, l’identification des signaux de dégradation de Rnt1p à l’échelle du transcriptome a permis de révéler plus de 384 transcrits clivés par Rnt1p, dont la majorité sont des ARN messagers. En outre, l’impact de la délétion de RNT1 sur l’expression de ces gènes est influencé par les conditions de culture des cellules, ce qui suggère que Rnt1p est un important régulateur conditionnel de l’expression génique. Somme toute, les résultats présentés dans cette thèse démontrent comment des ARNs sont spécifiquement choisis pour la dégradation et soulignent l’importance de la dégradation nucléaire dans la régulation de l’expression génique en réponse à des changements environnementaux. Mots clés = Rnt1p, RNase III, ARN double-brin, Saccharomyces cerevisiae, dégradation de l’ARN, régulation génique, réponse au glucose Studies of the mechanisms of selective RNA degradation by the RNase III of Saccharomyces cerevisiae By Mathieu Lavoie Département de microbiologie et d’infectiologie Thesis presented to the Faculté de médecine et des sciences de la santé for the obtention of the title of philosophiae doctor (Ph.D.) in microbiology, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, Canada, J1H 5N4 SUMMARY Precise modulation of gene expression is essential for any cell in order to regulate its metabolism and adapt to environmental changes. In fact, it is gene expression, rather than DNA sequence alone, which mostly explains the functional diversity and complexity between the different cell types. As such, gene expression mainly results from changes in the levels of cellular RNAs which are, in turn, dependent on the equilibrium between their relative rates of synthesis and degradation. While transcriptional control has been largely studied in the past, recent publications reveal that changes in RNA stability also play an important role in shaping the transcriptome. Unfortunately though, the mechanisms ensuring precise and selective RNA degradation remains poorly understood. In this thesis, I have used the yeast Saccharomyces cerevisiae ribonuclease III (Rnt1p) as a model to study how specific transcripts are targeted for degradation and evaluate its contribution to the regulation of gene expression. The results indicate that Rnt1p regulates gene expression using a broad specificity for structured RNA stem loops. Indeed, a new structural motif of Rnt1p permits discrimination of hairpins with specific sequence while blocking the binding of the generic RNA duplexes recognized by other members of the RNase III family. This highly specific mode of substrate recognition was found to be easily modulated by a flexible network of protein RNA interactions. On the other hand, transcriptome- wide identification of Rnt1p degradation signals uncovered more than 384 transcripts, including 291 mRNAs. Interestingly, the impact of RNT1 deletion on mRNA expression is modulated by changes in the growth conditions of the cell, indicating that Rnt1p is an important regulator of conditional gene expression. Overall, the results presented in this thesis demonstrate how specific RNAs are selected for degradation and highlight the importance of nuclear RNA decay for fine tuning gene expression in response to changes in growth conditions. Key words = Rnt1p, RNase III, double-stranded RNA, Saccharomyces cerevisiae, RNA degradation, regulation of gene expression, glucose response iv TABLE DES MATIÈRES RÉSUMÉ ii SUMMARY iii TABLE DES MATIÈRES iv LISTE DES TABLEAUX vii LISTE DES FIGURES viii LISTE DES ABRÉVIATIONS xi INTRODUCTION 1 1. La dégradation de l’ARN joue un rôle important dans la régulation de l’expression génique chez la levure Saccharomyces cerevisiae 1 1.1. L’expression des gènes est un processus complexe et régulé à plusieurs niveaux 1 1.2. La dégradation de l’ARN : un processus bien conservé 4 1.3. Les principaux rôles de la dégradation de l’ARN chez S. cerevisiae 7 1.4. La régulation et la spécificité de la dégradation de l’ARN 10 2. Rnt1p, l’unique RNase III chez S. cerevisiae 12 2.1. Les RNase III forment une famille conservée et ubiquitaire d’endoribonucléases spécifiques pour l’ARN double-brin 12 2.2. La structure protéique de Rnt1p et des RNase III 13 3. Rnt1p influence plusieurs aspects de la biologie de l’ARN chez S. cerevisiae 16 3.1. Expression et maturation de l’ARN ribosomal 17 3.2. La maturation des ARNno et ARNnu 17 3.3. Le contrôle de la qualité des ARNs non-épissés 18 3.4. La dégradation conditionnelle des ARNm 18 3.5. Sauvegarde de la terminaison de la transcription de l’ARN polymérase II 20 4. Rnt1p reconnaît et clive une structure particulière de l’ARN double- brin 21 4.1. Trois épitopes sur l’ARN modulent la réactivité des substrats de Rnt1p 21 4.2. Le dsRDB de Rnt1p reconnaît la structure adoptée par la tétra- boucle 24 5. Objectifs du projet 26 v CHAPITRE I : La ribonucléase III Rnt1p de Saccharomyces cerevisiae utilise un réseau de ponts hydrogènes pour lier et cliver ses substrats 28 Avant-propos 28 Résumé 29 Article 1 30 CHAPITRE II : Rnt1p utilise deux systèmes de mesure lors de la reconnaissance de ses substrats 70 Avant-propos 70 Résumé 71 Article 2 72 CHAPITRE III : Caractérisation des signaux de dégradation par la ribonucléase III Rnt1p à travers le génome de Saccharomyces cerevisiae 119 Avant-propos 119 Résumé 120 Article 3 121 CHAPITRE IV : Les produits de clivage d’un ARN messager rapporteur par Rnt1p sont exportés et dégradés au cytoplasme 177 Avant-propos 177 Résumé 178 Article 4 179 CHAPITRE V : Le couplage de la répression de la transcription et la dégradation de l’ARN permet la régulation de l’expression conditionnelle des gènes 206 Avant-propos 206 Résumé 207 Article 5 208 DISCUSSION 246 6. La reconnaissance des substrats par Rnt1p: entre flexibilité et spécificité 247 6.1. Rnt1p reconnaît la structure et la séquence de la tétra-boucle 247 6.2. La reconnaissance des substrats non-canoniques nécessite vraisemblablement un changement conformationnel de l’ARN 249 6.3. Rnt1p révèle un nouveau mode de reconnaissance de l’ARN par les RNase III 251 6.4. Un mécanisme d’action séquentiel assure la spécificité du clivage par Rnt1p 254 6.5. Différents éléments cis influencent la réactivité des substrats de Rnt1p 256 vi 7. L’impact fonctionnel de Rnt1p sur l’expression des gènes 260 7.1. Rnt1p régule l’expression et clive plusieurs ARNm 260 7.2. La dégradation nucléaire est impliquée dans régulation conditionnelle de l’expression génique 262 7.3. Rnt1p cible les voies métaboliques sensibles aux conditions environnementales 265 7.4. Rnt1p influence la transcription de certains gènes 266 7.5. La liaison de l’ARN indépendante du clivage laisse entrevoir un rôle non-catalytique de Rnt1p 269 8. Les mécanismes de régulation de l’activité de Rnt1p 269 8.1. Les interactions protéines-protéines influencent le clivage de l’ARN par Rnt1p 269 8.2. Le recrutement co-transcriptionnel de Rnt1p 271 8.3. La localisation subcellulaire de Rnt1p permettrait la régulation conditionnelle des gènes en fonction du cycle cellulaire 273 8.4. Les conditions de culture affectent le niveau d’expression de Rnt1p 273 8.5. Rnt1p semble être régulé au niveau post-traductionnel 274 9. À propos de la classification des RNase III 275 CONCLUSION 278 REMERCIEMENTS 281 LISTE DES RÉFÉRENCES 282 ANNEXES 297 vii LISTE DES TABLEAUX INTRODUCTION Tableau 1 : Liste non-exhaustive des principaux facteurs impliqués dans la dégradation de l’ARN chez S.
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