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Regulation of Alternative Splicing and Polyadenylation by Genotoxic Anti-Cancer Agents Iris Tanaka

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Regulation of Alternative Splicing and Polyadenylation by Genotoxic Anti-Cancer Agents Iris Tanaka Regulation of alternative splicing and polyadenylation by genotoxic anti-cancer agents Iris Tanaka To cite this version: Iris Tanaka. Regulation of alternative splicing and polyadenylation by genotoxic anti-cancer agents. Biochemistry, Molecular Biology. Université Paris Saclay (COmUE), 2019. English. NNT : 2019SACLS025. tel-02050405 HAL Id: tel-02050405 https://tel.archives-ouvertes.fr/tel-02050405 Submitted on 27 Feb 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Régulation de l’épissage et de la polyadenylation alternatifs par les 5 2 agents anticancéreux génotoxiques 0 S Thèse de doctorat de l'Université Paris-Saclay SACL 9 préparée à l’Université Paris-Sud : 201 École doctorale n°582 NNT Cancérologie : biologie – médecine – santé (CBMS) Spécialité de doctorat: aspects moléculaires et cellulaires de la biologie Iris Tanaka Composition du Jury : Robin Farhaeus DR1, Université Paris-Diderot (UMR 1131) Président Christiane Branlant DRCE Émerite, Université de Lorraine (UMR7365) Rapportrice Claudio Sette Associate Professor, Universitá Cattolica del Sacro Cuore Rapporteur Ken Olaussen MCU, Université Paris-Sud (UMR981) Examinateur Martin Dutertre CR1, Institut Curie (UMR3348) Directeur de thèse Université Paris-Saclay Espace Technologique / Immeuble Discovery Route de l’Orme aux Merisiers RD 128 / 91190 Saint-Aubin, France With the support of : ACKNOWLEDGMENTS - REMERCIEMENTS First, I would like to thank Pr. Claudio Sette and Dr. Christiane Branlant for kindly accepting to review my PhD thesis manuscript, as well as Dr. Robin Fahraeus and Dr. Ken Olaussen for arranging their schedules to attend my thesis defense. Thank you for agreeing to evaluate my PhD thesis work. Je vais maintenant continuer en français. Je remercie Stéphan de m’avoir accueilli dans son équipe, et Mounira dans son unité. Merci Stéphan pour les échanges toujours constructifs que nous avons eu. Merci Mounira pour ton accueil. Je me suis sentie valorisée en tant que jeune chercheuse dans l’UMR 3348. Je remercie bien sûr Martin, mon directeur de thèse, pour m’avoir soutenue dans ce travail au cours de ces (plus de) quatre années. Tu es un encadrant exceptionnel. J’ai beaucoup aimé travailler avec toi, et les (très) longues discussions sur les projets me manqueront sûrement. J’ai énormément appris à tes côtés. En effet je n’ai pas eu le sentiment de travailler pour toi, mais avec toi. Tu m’as considéré très vite comme une chercheuse à part entière malgré mon manque d’expérience dans le domaine de l’ARN et des dommages à l’ADN, ce qui m’a beaucoup donné confiance en moi. Tu t’es souvent soucié de mon équilibre personnel et tu as aussi su me soutenir discrètement dans les moments difficiles que j’ai traversés. Merci pour tout. Merci à toute l’équipe Vagner passée et présente, qui m’a permis d’aller au labo chaque jour avec la bonne humeur. Je pense particulièrement à Maricarmen, Michelle, Galina, Ludo qui étaient là au tout début quand je suis arrivée, et avec qui on a partagé quelques fous rires. Merci Sabrina, c’est aussi grâce à toi qu’il y a une bonne ambiance au labo, et que l’on rigole bien. Et puis bien sûr Sylvain, mon voisin de bureau quasi- communicant. Merci pour ta bonne humeur, les rigolades, et ta disponibilité. Merci à l’équipe Amor-Guéret, notamment Sandra, Rosine, Elias, et Hamza qui font partie intégrante de mon expérience dans l’UMR 3348, avec qui j’ai pu discuter science mais pas que. Merci Pascale, tu es devenue petit à petit comme une confidente, nos papotages me manqueront c’est sûr. Mes copines de l’UMR3348, vous savez qui vous êtes, mais je vais quand même faire quelques spéciale dédicaces. Ma Rymounette, tu dois être la première personne avec qui j’ai parlé en arrivant, et je ne pensais pas trouver une amie si chère pendant ma thèse. Même si tu es Docteure et que tu n’es plus à Orsay (vive la Tinisie), je pense que nos vies sont maintenant liées, et on a encore beaucoup de choses à partager. Hélène, je papote beaucoup plus depuis que tu es dans mon bureau, pour mon plus grand plaisir. Je trouve qu’on est un peu pareil, et ce que j’aime chez toi, c’est qu’on peut parler de tout. Alina my dear, I sure wasn’t expecting to meet a lifelong friend like you during my thesis. I really enjoyed going through pregnancy with you. We now have this special mommy connection and I am so grateful. Mélissa ma chérie, tu es la meilleure voisine de bureau que j’ai eu ! On a partagé beaucoup de choses ensemble, et j’espère que ça va continuer (surtout les pâtisseries). Géraldine, ton côté sensible me touche beaucoup, et je me suis toujours sentie en confiance avec toi. J’espère construire une petite famille qui rayonne d’amour comme la tienne. Virginie, la meuf la plus fit de l’unité ! Je ne me souviens plus comment on s’est rapprochées, mais je crois que c’était dans le RER, tu es venue me taper la discut. Heureusement que tu es plus extravertie que moi, sinon j’aurais peut-être raté une super amitié. Merci Christine et toute la famille Tencer, ma famille éloignée la plus proche ! Christine, tu sais que tu as une place toute particulière. Merci d’avoir toujours été là, dans tous les bon et mauvais moments. Je sais que je pourrai toujours compter sur toi. Merci Pépé, Mémé, Papa, et Maman. Je suis très fière d’avoir un petit bout de vous, et j’espère que je vous rends fiers aussi. Merci beaucoup Emmanuelle et Lucien, je ne pouvais pas rêver meilleurs beaux- parents. Merci infiniment pour votre aide ces derniers mois, et votre soutien depuis plus de 5 ans maintenant. C’est grâce à vous aussi que j’ai pu écrire cette thèse. Et le meilleur pour la fin… Merci Thomas. Quelle aventure… ! Merci de m’avoir soutenu, écouté, rassuré, encouragé toutes ces années. Merci d’avoir été là. Après avoir traversé cette thèse, rythmée par des bas très très bas, et des hauts très très hauts, je suis convaincue que l’on peut tout accomplir ensemble. Je ne pense pas qu’il existe quelqu’un qui me corresponde mieux que toi. Merci d’être un super papa, merci d’illuminer ma vie. Et enfin ma petite Lana, mon bébé, mon petit monkey, mon précieux, merci d’avoir chamboulé tout ça. Tu as transformé la rédaction de cette thèse en vrai challenge, mais tu m’as rendue plus forte. Tes sourires me font oublier tous mes soucis, merci d’être le meilleur bébé au monde. Regulation of alternative splicing and polyadenylation by genotoxic anticancer agents | Iris Tanaka Table of contents ABBREVIATIONS ....................................................................................................................................... 3 PREAMBLE ............................................................................................................................................... 5 INTRODUCTION ....................................................................................................................................... 6 I. Alternative splicing (AS) and polyadenylation (APA) in cancer ................................... 6 1) AS mechanisms and regulation in cancer ................................................................................ 6 a. Pre-mRNA splicing ...................................................................................................................... 6 b. AS regulation and physiological role .......................................................................................... 9 c. AS regulation in cancer ............................................................................................................. 13 2) APA mechanisms and regulation in cancer ........................................................................... 18 a. Pre-mRNA 3’ end processing .................................................................................................... 18 b. APA regulation .......................................................................................................................... 21 c. Impact of APA ........................................................................................................................... 23 d. APA regulation in cancer .......................................................................................................... 25 II. Response and resistance to genotoxic anticancer agents: focus on doxorubicin and cisplatin ................................................................................................................................. 27 1) Genotoxic anticancer agents ................................................................................................. 27 a. Genotoxic anticancer agents .................................................................................................... 27 b. DNA topoisomerase II poisons and mechanism of action ........................................................ 28 c. Platinum compounds and mechanism of action ...................................................................... 32 2) The cell response to genotoxic stress.................................................................................... 35 a. The DNA damage response
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