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DNA Damage and DNA Repair in Cancer Genomes

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DNA Damage and DNA Repair in Cancer Genomes DNA damage and DNA repair in cancer genomes Doctoral thesis at the Medical University of Vienna for obtaining the academic degree Doctor of Philosophy Submitted by Michel B.-B. Owusu, MSc Supervisor: Dr. Joanna Loizou CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences Lazarettgasse 14, AKH BT25.3 1090 Vienna, Austria Vienna, 08/2018 DNA damage and DNA repair in cancer genomes Michel B.-B. Owusu Declaration The experimental part of the work that I present here was carried out in the laboratory of Dr. Joanna Loizou, DNA damage signaling group, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. The computational data analysis part was carried out in the laboratory of Dr. Serena Nik-Zainal, Mutation Signatures group, Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, UK and Department of Medical Genetics, The Clinical School, University of Cambridge, Cambridge, UK. The project was conceived by Dr. Joanna Loizou, Prof. Stephen P. Jackson and Dr. Serena Nik-Zainal. The experimental part of the project was designed by Dr. Joanna Loizou and myself, with input from Mag. Marc Wiedner and Dr. Jana Stranska. I performed the experimental work and was assisted by Mag. Marc Wiedner and Dr. Jana Stranska with the cell culture work. Dr. Xueqing Zou performed the computational data analysis. Dr. Xueqing Zou and I contributed equally to this work. Project Coordination assistance was received from Dr. Rebecca Harris at the lab of Prof. Stephen P. Jackson, The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK. Dr. Serena Nik-Zainal, Dr. Xueqing Zou, Dr. Joanna Loizou and myself wrote the manuscript, with input from all authors. The resulting manuscript is my first-author publication that constitutes this thesis and has been reprinted according to the reprint and permission policies of the Nature Publishing Group. The article can be found in the Nature Communications journal: Validating the concept of mutational signatures with isogenic cell models. Xueqing Zou#, Michel Owusu#, Rebecca Harris, Stephen P. Jackson, Joanna I. Loizou* & Serena Nik- Zainal*. Nature Communications volume 9, Article number: 1744 (2018). https://doi.org/10.1038/s41467-018-04052-8 (# these authors contributed equally, * these authors are both corresponding authors) I, the author, wrote all the chapters of this thesis. ii DNA damage and DNA repair in cancer genomes Michel B.-B. Owusu Table of contents Declaration ............................................................................................................................. ii Table of contents .................................................................................................................. iii List of figures ........................................................................................................................ vi List of tables ......................................................................................................................... vi Abstract ................................................................................................................................ vii Zusammenfassung ............................................................................................................. viii Publications arising from this thesis.................................................................................. ix List of Abbreviations ............................................................................................................. x Acknowledgements ............................................................................................................ xiii CHAPTER ONE: INTRODUCTION ......................................................................................... 1 Our fight against cancer ................................................................................................... 1 Historic perspective ......................................................................................................... 1 What is cancer ................................................................................................................. 2 Epigenetic alterations ...................................................................................................... 3 Sequencing of genomes .................................................................................................. 3 Lessons from the human genome ................................................................................... 4 Current state in our fight against cancer .......................................................................... 4 Targeted approaches in cancer therapy .......................................................................... 5 Barriers against cancer ..................................................................................................... 6 Tissue and cellular barriers ............................................................................................. 6 Genomic barriers ............................................................................................................. 7 DNA synthesis & replication ............................................................................................ 8 DNA synthesis ................................................................................................................. 8 DNA replication ................................................................................................................ 9 DNA damage .................................................................................................................... 10 DNA damage response ................................................................................................... 11 DNA repair ........................................................................................................................ 12 Polymerases in DNA repair ........................................................................................... 13 Mismatch repair (MMR) ................................................................................................. 13 Direct reversal / repair (DR) ........................................................................................... 14 Base excision repair (BER) ........................................................................................... 16 Nucleotide excision repair (NER) .................................................................................. 17 iii DNA damage and DNA repair in cancer genomes Michel B.-B. Owusu Double-strand break repair (DSBR) .............................................................................. 18 Homologous recombination (HR) / Homology directed repair (HDR) ............................ 20 Non-homologous end joining (NHEJ) ............................................................................ 20 Fanconi Anemia (FA) pathway of repair ........................................................................ 21 DNA damage & DNA damage response in cancer therapy ......................................... 22 DNA damage and cancer therapy ................................................................................. 22 Exploiting DNA repair in cancer therapy ........................................................................ 22 Cancer genomes .............................................................................................................. 23 Mutations in cancer genes ............................................................................................. 23 Why we look for mutation patterns ................................................................................ 23 Mutation patterns in cancer genomes ........................................................................... 25 Mutation signatures: a brief history and explanation ..................................................... 27 Algorithms for analyzing mutation signatures ................................................................ 28 Types of patterns / mutation signatures in the genome .............................................. 32 Base substitutions ......................................................................................................... 32 Insertions / deletions (indels) ......................................................................................... 34 Rearrangements ............................................................................................................ 34 Other structural or topographical changes .................................................................... 35 Mutation signatures & molecular markers in cancer ................................................... 36 Mutation signatures as markers of biological processes ............................................... 36 Re-categorizing cancer with mutation signature analysis .............................................. 37 Modelling mutation signatures in vitro ......................................................................... 38 Motivation ...................................................................................................................... 38 Strategy ......................................................................................................................... 39 Aims of this thesis ........................................................................................................... 40 CHAPTER TWO: RESULTS
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