Rôles Et Régulations De Polo Et Bubr1 Sur Les Cassures Double-Brin De L'adn En Mitose

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Rôles Et Régulations De Polo Et Bubr1 Sur Les Cassures Double-Brin De L'adn En Mitose THÈSE Présentée à L’UNIVERSITÉ DE BORDEAUX ÉCOLE DOCTORALE SCIENCES DE LA VIE ET DE LA SANTÉ Par Cédric LANDMANN POUR OBTENIR LE GRADE DE DOCTEUR Rôles et régulations de Polo et BubR1 sur les cassures double-brin de l'ADN en mitose SPÉCIALITÉ : Biologie Cellulaire et Physiopathologie Soutenue publiquement le : 15 Décembre 2017 Membres du jury Sophie JAVERZAT - PR, Université de Bordeaux, Président du jury Olivier GAVET - MCU, HDR, Université Pierre et Marie Curie, Rapporteur Julien DUMONT - DR2, Université Paris Diderot, Rapporteur Allison BARDIN - DR2, Université Pierre et Marie Curie, Examinateur Anne ROYOU - DR2, Université de Bordeaux, Directrice de thèse Emilie MONTEMBAULT - CR2, Université de Bordeaux, Membre invité Remerciements Le travail de recherche présenté dans cette thèse a été effectué à l’Institut Européen de Chimie et de Biologie sous la direction du docteur Anne ROYOU. Je remercie Anne pour m’avoir motivé et permis de d’effectuer cette thèse dans son équipe. Je la remercie pour m’avoir encadré, pour m’avoir permis de me former, en biologie mais aussi en microscopie ou en informatique, ainsi que pour la bonne ambiance qu’elle a permis d’instaurer dans l’équipe. Je remercie également Emilie Montembault, qui m’a initialement recruté dans le laboratoire comme assistant ingénieur, qui m’a conseillé et encadré pendant ces années passées au laboratoire, et qui m’a beaucoup aidé pour l’écriture de ce manuscrit, même pendant ses vacances. Merci aux collègues, Damien, Jérôme, James, Lou, Macha, Priscillia pour leur aide, pour leur bonne humeur, pour tous les bons moments qu’on a passé ensemble pendant les sorties labo ou pendant les happy-hours. Merci à ma famille, mes parents, mon frère et mes grands-parents qui m’ont toujours soutenu et qui m’ont permis d’en arriver là. Merci à tous mes amis. Merci à Malo et Saucisse qui m’ont soutenu dans les moments difficiles. Merci à Hélène pour m’avoir poussé et pour m'avoir fait croire en moi. Merci à Mélissa, avec qui on aura passé des « soirées de folie, etc » à boire du thé et du café lors de la rédaction de la thèse. Pour finir, je remercie les membres du jury, Sophie JAVERZAT, Olivier GAVET, Julien DUMONT et Allison BARDIN, d’avoir accepté de juger mon travail. TABLE DES MATIERES Introduction ................................................................................................................................ 1 Chapitre 1 : La mitose, étape du cycle cellulaire ..................................................................... 3 I. Déroulement du cycle cellulaire et de la mitose ............................................................... 3 II. Régulation de la mitose ................................................................................................... 6 A. L’entrée en mitose est sous le contrôle de CDK1 ....................................................... 6 B. Sortie de mitose : le rôle de l’APC/C .......................................................................... 8 1. APC/C et cofacteurs ................................................................................................. 8 2. Dégradations en début d’anaphase par APC/CCDC20 ................................................ 8 3. Dégradations en fin de mitose par APC/CCDH1 ........................................................ 9 III. La ségrégation des chromosomes ................................................................................ 10 A. Structure de la chromatine en mitose ........................................................................ 10 1. Les nucléosomes .................................................................................................... 10 2. Les condensines ..................................................................................................... 10 3. Les cohésines ......................................................................................................... 11 B. Le fuseau mitotique ................................................................................................... 12 1. Les microtubules .................................................................................................... 12 2. Le centrosome ........................................................................................................ 12 3. Autres centres de nucléations des microtubules .................................................... 13 4. Facteurs facilitant la formation du fuseau mitotique ............................................. 13 5. Le fuseau mitotique ............................................................................................... 14 C. Le kinétochore ........................................................................................................... 15 1. Structure du kinétochore ........................................................................................ 16 a. Centromère ......................................................................................................... 16 b. Inner kinétochore ............................................................................................... 17 c. Outer kinétochore ............................................................................................... 17 d. Corona fibreuse .................................................................................................. 19 2. Fonctions du kinétochore ....................................................................................... 19 a. Interaction kinétochore-microtubules ................................................................ 19 b. Correction de l’attachement kinétochore-microtubules ..................................... 20 c. Point de contrôle du fuseau mitotique (SAC) .................................................... 22 i. Composants du SAC ....................................................................................... 22 ii. Mise en place du SAC ................................................................................... 23 iii. Inhibition de l’APC/C ................................................................................... 24 iiii. Inactivation du SAC .................................................................................... 26 Chapitre 2 : Les régulateurs mitotiques ................................................................................. 29 I. La famille des Polo-like kinases (Plks) .......................................................................... 29 A. Structure .................................................................................................................... 29 B. Activation de Polo ..................................................................................................... 31 C. Localisation de Polo au cours du cycle cellulaire ..................................................... 32 1. Recrutement au centrosome ................................................................................... 33 2. Recrutement au kinétochore .................................................................................. 33 3. Recrutement sur les microtubules .......................................................................... 34 4. Recrutement sur le site d'abscission ...................................................................... 34 D. Rôles de Polo ............................................................................................................ 35 1. Régulation de l’entrée en mitose ........................................................................... 35 2. Régulation de l’APC/C .......................................................................................... 35 3. Fonctions aux centrosomes .................................................................................... 36 4. Fonctions aux centromères/kinétochores ............................................................... 36 5. Cohésion des chromatides sœurs ........................................................................... 37 6. Cytocinèse et abscission ........................................................................................ 38 II. BubR1 ........................................................................................................................... 38 A. Structure de BubR1 ................................................................................................... 39 1. Domaine KEN ........................................................................................................ 39 2. Domaine "Bub3 Binding Domain" ........................................................................ 40 3. Phe-box et D-box ................................................................................................... 40 4. Domaine 3 .............................................................................................................. 40 5. Domaine KARD .................................................................................................... 40 6. Domaine kinase ...................................................................................................... 41 B. Localisation de BubR1 à travers le cycle cellulaire .................................................. 42 1. Recrutement de BubR1 aux kinétochores .............................................................. 42 2. Les rôles de BubR1 ................................................................................................ 43 a. Le rôle de BubR1 dans le SAC .........................................................................
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