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The FOXM1/BRIP1 Axis in Replicative Stress Induced DNA Damage Response in Neuroblastoma

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The FOXM1/BRIP1 Axis in Replicative Stress Induced DNA Damage Response in Neuroblastoma Ghent University, Faculty of Medicine and Health Sciences The FOXM1/BRIP1 axis in replicative stress induced DNA damage response in neuroblastoma: functional exploration and zebrafish modeling This thesis is submitted as fulfillment of the requirements for the degree of Doctor in Health Sciences by Suzanne Vanhauwaert, 2017 Promoter: Prof. dr. Frank Speleman Co-promoter: Prof. dr. Katleen De Preter I II Thesis submitted to fulfill the requirements for the degree of Doctor of Health Sciences Promoter Prof. dr. Frank Speleman Department of Pediatrics and Medical Genetics, Ghent University, Ghent, Belgium Co-promoter Prof. dr. Katleen De Preter Department of Pediatrics and Medical Genetics, Ghent University, Ghent, Belgium Members of the examination committee Shizhen Zhu MD, PhD Mayo Clinic, 200 First St. SW Rochester, MN 55905 Rochester, Minnesota, USA Anna Sablina, PhD VIB-KU Leuven Center for Cancer Biology O&N 4, Leuven, Belgium Kathleen Claes, PhD Department of Pediatrics and Medical Genetics, Ghent University, Ghent, Belgium Tom Van Maerken, MD, PhD Department of Pediatrics and Medical Genetics, Ghent University, Ghent, Belgium Steven Goossens, PhD Department of Pediatrics and Medical Genetics, Ghent University, Ghent, Belgium Joni Van der Meulen, PhD Department of Pediatrics and Medical Genetics, Ghent University, Ghent, Belgium Statement of confidentiality: The information in this document is confidential to the person to whom it is addressed and should not be disclosed to any other person. It may not be reproduced in whole, or in part, nor may any of the information contained therein be disclosed without the prior consent of the author. The research described here was conducted at the Center for Medical Genetics (Ghent University, Ghent, Belgium) and Dana Farber Cancer Institute (Harvard Medical School, Boston, USA) and funded by grants from the Research Foundation Flanders (FWO), the Flemish League against Cancer (VLK) and Villa Joep. III IV Table of content Table of content ...................................................................................................................................... V List of abbreviations: ............................................................................................................................. VII PART I: introduction ............................................................................................................................... IX Introduction: ............................................................................................................................................ 1 Neuroblastoma .................................................................................................................................... 1 A little bit of history… ...................................................................................................................... 1 NB: when development goes wrong ................................................................................................ 2 NB: an embryonal precancer ........................................................................................................... 2 The NB genomic landscape ................................................................................................................. 3 DNA copy number alterations ......................................................................................................... 3 Chromosome 17q driver genes in NB .............................................................................................. 5 Mutations/single base pair variants................................................................................................ 6 Genetic predisposition to NB ........................................................................................................... 7 Zebrafish .............................................................................................................................................. 9 Zebrafish as a model organism ....................................................................................................... 9 Zebrafish and its cancer models ...................................................................................................... 9 Zebrafish, more than a cancer model… ......................................................................................... 10 Replicative stress and cancer ............................................................................................................ 13 DNA replication stress ................................................................................................................... 13 Replication stress and cancer: the story of Jekyll and Hide ........................................................... 15 Replication stress as a new cancer hallmark ................................................................................. 16 BRIP1 (alias FANCJ or BACH1)............................................................................................................ 18 BRIP1: the BRCA1 binding protein ................................................................................................. 18 BRIP1 is a Fanconi anemia gene .................................................................................................... 19 BRIP1 as a potential tumor suppressor gene ................................................................................ 20 BRIP1 and interstrand crosslink (ICL) repair .................................................................................. 20 BRCA1 and its binding partner BRIP1 ............................................................................................ 21 The helicase function of BRIP1 ...................................................................................................... 22 FOXM1: a central regulator of cell cycle and DNA damage .............................................................. 24 FOXM1 in normal development and disease ................................................................................. 24 Molecular targeting of FOXM1 ...................................................................................................... 26 V The role of FOXM1 in the DNA damage response ......................................................................... 27 The G4 genome ................................................................................................................................. 29 G4-DNA ........................................................................................................................................... 29 G4 structures regulate transcription and translation .................................................................... 30 G4 structures in replication and genome instability and the role of BRIP1 ................................... 31 Targeting G4 structures ................................................................................................................. 32 References: ........................................................................................................................................ 34 PART II: Research Objectives ................................................................................................................. 45 Research objectives: .............................................................................................................................. 47 PART III: Results ..................................................................................................................................... 49 Chapter 3: BRIP1 overexpression accelerates MYCN driven neuroblastoma formation and is part of a FOXM1 driven gene signature providing protection to excessive replicative stress ............................ 51 Chapter 4: A MYCN activated FOXM1 driven embryonal pathway defines therapy resistant neuroblastoma patients and marks FOXM1 as target for future drug screening ................................. 81 Chapter 5: Molecular targeting of FOXM1 in neuroblastoma cells..................................................... 119 Chapter 6: Expressed repeat elements improve RT-qPCR normalization across a wide range of zebrafish gene expression studies....................................................................................................... 131 PART IV: Discussion ............................................................................................................................. 161 Discussion and future perspectives ..................................................................................................... 163 PART V: Summary, Samenvatting, CV ................................................................................................. 181 Summary: ............................................................................................................................................ 183 Samenvatting:...................................................................................................................................... 185 Curriculum Vitae .................................................................................................................................. 187 Dankje wel... ........................................................................................................................................ 194 VI List of abbreviations: ALK Anaplastic lymphoma kinase receptor tyrosine kinase AML Acute myeloid leukemia BACH1 Brca1-Associated
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