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Functional Interaction Between the DNA Damage Tolerance Pathway and the DNA Damage Checkpoint : Implications for Genome Stability and Oncogenesis Chames Kermi

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Functional Interaction Between the DNA Damage Tolerance Pathway and the DNA Damage Checkpoint : Implications for Genome Stability and Oncogenesis Chames Kermi Functional interaction between the DNA damage tolerance pathway and the DNA damage checkpoint : implications for genome stability and oncogenesis Chames Kermi To cite this version: Chames Kermi. Functional interaction between the DNA damage tolerance pathway and the DNA damage checkpoint : implications for genome stability and oncogenesis. Biochemistry, Molecular Bi- ology. Université Montpellier, 2016. English. NNT : 2016MONT3520. tel-01633798 HAL Id: tel-01633798 https://tel.archives-ouvertes.fr/tel-01633798 Submitted on 13 Nov 2017 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. Délivré par l’Université de Montpellier Préparée au sein de l’école doctorale Sciences Chimiques et Biologiques pour la Santé Et de l’unité de recherche Institut de Génétique Humaine UPR1142 Spécialité : Biochimie et biologie moléculaire Présentée par M. Chames KERMI Interactions fonctionnelles entre le système de tolérance des lésions et le checkpoint des dommages à l'ADN : Conséquences sur la stabilité du génome et l'oncogenèse Soutenue le 14 Décembre 2016 devant le jury composé de Pr. Barbara Van Loon , PU, Norwegian University of Rapporteur Science and Technology, Trondheim Dr. Jacek Kubiak , DR2, CNRS, Institut de génétique Rapporteur et développement de Rennes Dr. Agnès Cordonnier , CR1, INSERM, Institut de Examinateur recherche de l’Ecole de biotechnologie de Strasbourg Dr. Jean Philippe Hugnot , MCU, Institut de Examinateur neurosciences de Montpellier Dr. Domenico Maiorano , DR2, INSERM, Intitut de Directeur de Thèse Génétique Humaine, Montpellier “Ex ovo omnia” “Everything comes from an egg” William Harvey (1578-1657) The important thing is not to stop questioning. Curiosity has its own reason for existing. Albert Einstein (1879-1955) 3 Functional interactions between the DNA damage tolerance pathway and the DNA damage checkpoint: Implications for genome stability and oncogenesis 5 Aknowledgments First of all, I would like to express my gratitude to my Ph.D. advisor Dr. Domenico Maiorano for welcoming me in his laboratory, for continuous support during my Ph.D, for his patience, motivation, and immense knowledge. His guidance helped me in all the time of research and for writing this thesis. With him I spent four great years full of fascinating science and fun. I grew up personally and scientifically and learned a lot. I am glad to have been a member of his team. Domenico, thank you for believing in me, for your mentorship and constant encouragement. I appreciated very much the freedom you gave me to handle my projects and explore different aspects of science, expressing my personal opinion and curiosity in science. I have accumulated a lot of experience in your lab, and I believe I must be ready for new scientific challenges around the world. Besides my advisor, I would like to thank my thesis jury for accepting to evaluate my work, including the reporters Pr. Barbara Van Loon and Dr. Jacek Kubiak who kindly accepted to make a long journey all the way down to Montpellier to be part of this jury and dedicate time to go through my thesis and offer their valuable feedback to ameliorate it. I am also very grateful to the examiners Dr. Agnès Cordonnier for accepting to be part of the jury, and Dr. Jean Philippe Hugnot for the interesting advises concerning the glioblastoma project. I would like to thank also my thesis committee members, Dr. Philippe Pasero, Dr. Olivier Coux and Dr. Serge Roche for the insightful discussions and comments during my PhD committees, and who helped me a lot to shape my project along these past four years. Special thanks to Philippe Coulombe, who helped me a lot when I started and took me through exciting scientific adventures during our collaboration on CDT1 project. It was a great honour to work with you, Philippe, and I learned a lot from you. I also wish to thank all the former members of the lab who all contributed to the pleasant working atmosphere. Thank you Siem, for bringing a dynamic and funny environment in the lab, for all your help with experimental issues. I hope you will improve your football skills and you will be a perfect man. Many thanks to Dana, Majid, Elenora, and Nikolay whom I miss a lot and I am always so glad to see again. Thank you Susana for starting this exciting RAD18 project. 7 I also wish to acknowledge all the current members of the lab: Sofian, the young father, thank you for the funny moments and being a good friend. I wish all the best for your career, take care of your little family! Elena, keep your smile and your fun, I wish you the best of luck in the remainder of your thesis, you’re the next one, good luck. Lenka, despite you are a new member, your kindness and smile make me feel you always been part of the lab. Thank you for your support, for critical reading of my thesis and useful remarks. I’m sure you will do a great job!! Kamar, oh sorry Kalamar!! To be honest with you, when I saw you for the first time, I didn’t expect you to be as funny as you are. Thank you for cheering up my days with you sweet character and bringing good atmosphere to the lab. Overall I would like to thank all the people in IGH for their helpfulness and kindness, and for being a very cosy scientific neighbourhood, you made the institute a great place to be. Special Thanks to the basement people: Jessica, Guillaume, Mathilde, Kasia, Carolina, Nathalia, Marianne, Gohei, Ana-luiza. Thank you “big Lebowski” Kris for your advises, funny jokes and deep discussions. You are a great friend, and not only on the football pitch. A big thank to Sophie for being such a nice friend all along my thesis. Thank you for your smile, your encouragements and your support. I wish you all the best for your medicine studies (yes you can!!). Many thanks to my better half and future wife Nesrine, who was of great help and support during the hard times of my thesis and my life in general. Without you, I would have never started a PhD and probably never moved to France. You have been always next to me, pushing me up, encouraging me to give the best of myself. I’m really very grateful, you changed my life. Nesrine, I’m proud of you and what you have accomplished so far and I’m sure that the best is next!! Last but not the least, I would like to thank my family: my parents, my brother Nassim and my sister Lynda Inesse for always supporting me spiritually throughout my adventures. Without you and your encouragement in the hardest moments, none of this would be possible. Thank you for putting so much trust in me. 8 Table of Contents I. Introduction ........................................................................... 25 1. DNA Damage: A Threat to Genome Integrity .................................................................... 25 1.1. Endogenous DNA damage ............................................................................................................... 25 1.2. Exogenous DNA damage ................................................................................................................. 30 2. The cell response to DNA damage .................................................................................... 33 2.1. Checkpoint activation ...................................................................................................................... 33 2.2. DNA repair ....................................................................................................................................... 41 3. DNA replication: Duplication of the Genome .................................................................... 53 3.1. Historical overview of DNA replication model ................................................................................ 53 3.2. Origins of DNA replication ............................................................................................................... 55 3.3. Initiation of DNA Replication ........................................................................................................... 57 3.4. Priming and recruitment of DNA polymerases ............................................................................... 63 3.5. Elongation of DNA replicon ............................................................................................................. 65 3.6. Termination of DNA replication ...................................................................................................... 67 3.7. Regulation of DNA replication ......................................................................................................... 69 3.8. Regulation of DNA replication during early embryonic cleavages .................................................. 77 4. DNA damage tolerance pathways .................................................................................... 88 4.1. Translesion DNA Synthesis: error prone damage tolerance pathway ............................................ 89 4.2. Template switch: error-free damage tolerance pathway ............................................................. 100 4.3. Fork restart ...................................................................................................................................
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