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Thesis Reference Thesis Mechanisms of tumour suppression and control of genomic integrity by BARD1 JEFFORD, Charles Edward Abstract BARD1 est un suppresseur de tumeur qui interagit avec BRCA1 dans le maintien de l'intégrité du génome. D'autre part, il peut agir, indépendamment de BRCA1, dans une signalisation apoptotique en cas de stress génotoxique. Dans un premier volet, les mécanismes de suppression tumorale contrôlée par BARD1 ont été étudiés. Les régions de BARD1 nécessaires à l'induction de l'apoptose ont été identifiées ainsi que la nécessité d'une interaction entre BARD1 et p53. BARD1 est localisé dans le noyau où il forme des agrégats moléculaires avec BRCA1 et Rad51 pendant la réparation de l'ADN. En revanche, pendant l'apoptose, une translocation de BARD1 dans le cytoplasme a été observée. Dans un deuxième volet, certains facteurs déterminants de la stabilité chromosomique lors de la mitose ont été identifiés. En effet, lors de l'anaphase, BARD1 est localisé sur les microtubules, puis, lors de la cytokinèse, il interagit avec BRCA2, AuroraB et TACC1. Ces observations suggèrent un rôle supplémentaire de BARD1 dans la ségrégation des chromosomes pendant la mitose. Reference JEFFORD, Charles Edward. Mechanisms of tumour suppression and control of genomic integrity by BARD1. Thèse de doctorat : Univ. Genève, 2005, no. Sc. 3651 URN : urn:nbn:ch:unige-3490 DOI : 10.13097/archive-ouverte/unige:349 Available at: http://archive-ouverte.unige.ch/unige:349 Disclaimer: layout of this document may differ from the published version. 1 / 1 UNIVERSITÉ DE GENÈVE Département de biologie moléculaire FACULTÉ DES SCIENCES Professeur U. Schibler Département de réhabilitation et gériatrie FACULTÉ DE MÉDECINE Professeur K.-H. Krause Docteur I. Irminger-Finger Mechanisms of Tumour Suppression and Control of Genomic Integrity by BARD1 THÈSE Présenté à la faculté des sciences de l’Université de Genève pour obtenir le grade de Docteur ès sciences, mention biologique par Charles Edward Jefford de Troinex (GE) Thèse N° 3651 Genève, 2005 UNIVERSITÉ DE GENÈVE Département de biologie moléculaire FACULTÉ DES SCIENCES Professeur U. Schibler Département de réhabilitation et gériatrie FACULTÉ DE MÉDECINE Professeur K.-H. Krause Docteur I. Irminger-Finger Mechanisms of Tumour Suppression and Control of Genomic Integrity by BARD1 THÈSE Présenté à la faculté des sciences de l’Université de Genève pour obtenir le grade de Docteur ès sciences, mention biologique par Charles Edward Jefford de Troinex (GE) Thèse N° 3651 Genève, 2005 FACULTÉDESSCIENCES .. DE GENEVE Doctorat ès sciences mention biologique Thèse de Monsieur Charles Edward JEFFORD intitulée: "Mechanisms of Tumour Suppression and Control of Genomic Integrity by BARD1 Il La Faculté des sciences, sur le préavis de Monsieur K.-H. KRAUSE,professeur ordinaire et directeur de thèse (Département de gériatrie - laboratoire de biologie du vieillissement), de Madame 1.IRMINGER-FINGER,docteur (Département de gériatrie - laboratoire de biologie du vieillissement), et U. SCHIBLER,professeur ordinaire (Département de biologie moléculaire) co-directeurs de thèse, et M. AGUET, professeur (Institut Suissede recherche expérimentale surle cancer - Epalinges,Suisse),autorisel'impressionde la présente thèse, sans exprimer d'opinion sur les propositions qui y sont énoncées. Genève, le 18 août 2005 (1 ~ Y'" \Vl V' Thèse - 3651 - Le Doyen, Pierre SPIERER N.B.- La thèse doit porter la déclaration précédente et remplir les conditions énumérées dans les "Informations relatives aux thèses de doctorat à l'Université de Genève". Nombre d'exemplaires à livrer par colis séparé à la Faculté: - 7 - This thesis is dedicated to the ones I love: to my family and especially to my parents who unstintingly supported me throughout my university years. ii Acknowledgements I would like to thank my thesis supervisor and director, Dr Irmgard Irminger-Finger, for being such an excellent guide through this thesis and for her continuous enthusiasm; Professor Karl-Heinz Krause for being my thesis director and for welcoming me in the Laboratory of Aging Biology. I would like to thank Professors Ueli Schibler and Michel Aguet for accepting to be my thesis jury; Dr Pedro Herrera and Dr Michael Pepper for accepting to be my “parrains de thèse”. I would like to address my appreciation to Dr Anis Feki, Dr Esther Bettiol, Dr Laetitia Cartier-Fioraso and Dr Stephan Ryser for their friendship, advice and support; to Aurélie Caillon, Laura Ortolan-Trigui, Chantal Genet, Terese Laforge and Olivier Plastre for their kindness, support and excellent technical assistance; Dr Jacques Proust and Dr Sophie Clement-Leboube for helpful comments on the manuscript; and Hélène Gfeller-Tillmann for administrative help. I would like to thank Dr Sarantis Gagos for providing his expertise on cytogenetic analysis, Dr Jean Harb on electronic microscopy, Dr Serge Arnaudeau on confocal microscopy, Dr Bénédicte Delaval and Dr Daniel Birnbaum for their precious collaboration. I would like to give credit to all previous and present members of the Laboratory of Aging Biology and collaborators who helped me in various ways: Dr Marisa Jaconi, Dr Michel Dubois-Dauphin, Dr Lena Serrander, Dr Igor Bondarev, Dr Gaetan Gavazzi, Dr Philippe Berardi, Dr Jian Li, Dr Botond Banfi, Dr Mathieu Hauwel, Dr Michela Schaeppi, Dr Karen Bedard, Dr Anne-Thérèse Vlastos, Nicolas Molnarfi, Stéphanie Julien, Dr David Suter, Michael Stouffs, Fabrice Calabria, Mamadou Hadi-Sow, Dr Jian Yu Wu, Christine Deffert, Diderik Tirefort, Paula Borel, Françoise Piotton and Silvia Sorce. iii Furthermore, I would like to acknowledge my former mentors Dr Richard Isbrucker, Dr Ross Longley and Dr Shirley Pomponi at the Harbor Branch Oceanographic Institution in Florida who were instrumental in rekindling my interest in biological sciences during a fulfilling internship, as well as Mr J. S. Johnson who provided the opportunity to work at HBOI. Finally, I would like to express my gratitude to my father, Professor Charles William Jefford, for his unstinting support and encouragement, and for kindly reading the manuscript. I would also like to acknowledge my mother, sisters, nieces and brothers- in-law for their constant support: Susan, Sarah, Alex, Kasmira, Nina, Nieve, Mikael and Hossein without whom this doctorate would certainly not have been possible. iv TABLE OF CONTENTS page Avant propos. 1 Organisation de la thèse. 1 Résumé de la thèse . 2 Introduction sur BARD1 . 2 Structure de BARD1. 2 Les modèles génétiques . 3 L’activité ubiquitine ligase de BARD1. 3 Les fonctions de BARD1 dépendantes de BRCA1. 4 Les fonctions de BARD1 indépendantes de BRCA1. 5 Les objectifs de la thèse. 5 Résultats et discussion. 6 Conclusion. 13 Preface. 14 The purpose of cancer. 14 Review on BARD1 and its diverse functions. 16 I) Breast cancer and the BRCA tumour suppressors. 16 BRCA1 and BRCA2 mutations in cancer. 16 Genetic models for BRCA1 and BRCA2. 18 Overview BRCA1 and BRCA2 functions. 18 II) BARD1 protein structure . 19 BARD1 discovery and phylogenetic analysis. 19 BARD1 orthologues. 21 RING finger domain. 23 Ankyrin repeats. 25 BRCT domains. 25 III) Ubiquitin ligase functions of BRCA1/BARD1. 26 RING finger domain proteins are ubiquitin ligases. 26 Ubiquitination and de-ubiquitination. 26 BARD1/BRCA1 heterodimer is an E3 ubiquitin ligase. 27 Ubiquitin targets of the BARD1/BRCA1 heterodimer. 28 IV) BARD1 functions and its associated proteins. 31 v Knockout experiments and genomic instability phenotype. 32 BARD1 in DNA-damage repair. 33 Cellular localisation of BARD1 and BRCA1 during DNA repair. 33 BARD1 in transcriptional regulation and chromatin remodelling. 34 BARD1 in mRNA processing. 36 BRCA1-independent pro-apoptotic functions of BARD1 . 37 Mapping of pro-apoptotic domain of BARD1. 39 BRCA1 and BARD1 functions in cell cycle. 40 V) BARD1 mutations and expression in cancer. 41 BARD1 tumour suppressor mutations in breast and ovarian cancers 41 BARD1 expression in normal and tumour tissues. 43 VI) Conclusion. 45 Results. 47 Published results (1 to 4) and paper submitted for publication (5) are preceded by a one page summary and explain my contribution in each project. Supplemental results (6 and 7) are summarized and accompanied by figures. Publications: 1. Irminger-Finger I, Leung WC, Li J, Dubois-Dauphin M,Harb J, Feki A, Jefford CE, Soriano JV, Jaconi M, Montessano R, Krause KH. Identification of BARD1 as mediator between proapoptotic stress and p53-dependent apoptosis. Mol Cell. 2001 Dec;8(6):1255-66. 48 2. Jefford CE, Feki A, Harb J, Krause KH, Irminger-Finger I. Nuclear- cytoplasmic translocation of BARD1 is linked to its apoptotic activity. Oncogene. 2004 Apr 29;23(20):3509-20. 60 3. Feki A, Jefford CE, Durand P, Harb J, Lucas H, Krause KH, Irminger-Finger I. BARD1 expression during spermatogenesis is associated with apoptosis and hormonally regulated. Biol Reprod. 2004 Nov;71(5):1614-24. 73 4. Feki A, Jefford CE, Berardi P, Wu JY, Cartier L, Krause KH, Irminger- Finger I. BARD1 induces apoptosis by catalyzing phosphorylation of p53 by DNA-damage response kinase. Oncogene. 2005 Mar 14 (in press). 85 vi Submitted for publication: 5. Jefford CE, Delaval B, Ryser S, Birnbaum D, Irminger-Finger I. BARD1 interacts with BRCA2 to regulate cytokinesis and maintain genomic stability. 97 Supplemental results and ongoing projects: 6. Role of BARD1 in telomere maintenance and crisis. 124 7. BARD1 promoter analysis. 130 Conclusion. 136 References. 137 vii Avant propos Organisation de la thèse Quelques mots sont nécessaires pour décrire le plan de la thèse. La thèse est divisée en plusieurs parties. Le premier chapitre est en français, résume toute la thèse et constitue aussi l’introduction de thèse. Il contient un résumé de la revue sur BARD1, les objectifs et le plan de la thèse, un résumé précis des résultats et discussions, divisés en 7 sous-chapitres, ainsi qu’une petite conclusion. Le reste de la thèse est en anglais à cause des publications. Le deuxième chapitre est une préface philosophique sur le rôle des tumeurs dans la population. Le troisième chapitre est une revue complète sur BARD1 qui sera prochainement soumis pour une publication dans un journal et qui a déjà servi en partie comme chapitre pour un livre.
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