Role of nucleotide excision repair factors in genome maintenance in human cells under oxidative stress

ROLE OF NUCLEOTIDE EXCISION REPAIR FACTORS IN GENOME MAINTENANCE IN HUMAN CELLS UNDER OXIDATIVE STRESS LOW KAH MUN, GRACE BACHELOR OF SCIENCE (HONS) NATIONAL UNIVERSITY OF SINGAPORE A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF PHYSIOLOGY, YONG LOO LIN SCHOOL OF MEDICINE NATIONAL UNIVERSITY OF SINGAPORE 2010 ACKNOWLEDGEMENTS First and foremost, I would like to express my heartfelt gratitude to my supervisor, Assoc Prof M Prakash Hande for his patience, guidance and support throughout the course of my graduate program His zeal and dedication to research has never ceased to encourage me I would also like to extend my warmest thanks to all the members, past and present, of the Genome Stability Laboratory for their support, encouragement and friendship, of which were integral in creating the conducing environment for working and learning Of special mention is Mr Jayapal Manikandan, who analysed the raw data for the microarray experiments Also to thank sincerely are Mr Aloysius Ting Poh Leong, former colleague, Mr Edwin Dan Fok Zhihao, former honours student, and Mr Khaw Aik Kia, colleague Their friendship, support, constructive and invaluable criticisms have helped tremendously in the course of this thesis Dr A.S Balajee, Center for Radiological Research, College of Physicians and Surgeons, Columbia University, New York, U.S.A., is thanked for his help with setting up the Comet assay in the laboratory I thank the Molecular and Cellular Immunology Laboratory for providing the equipment and reagents for the RT-PCR experiment Special thanks to Dr Moizza Mansoor for her time rendered I also thank the Apoptosis and Cancer Biology Laboratory for the gift of some of the antibodies To Dr M.Y.G Tan, I extend my deepest thanks for critically reading my introduction and assisting in the formatting of the document i Importantly, I would like to express my sincere appreciation to my examiners for taking the time and effort to examine this thesis For the unconditional understanding and love, I am grateful to my supportive family Last but not least, I thank the National University of Singapore, Yong Loo Lin School of Medicine and the Department of Physiology for the opportunity and support given throughout the course of this thesis ii TABLE OF CONTENTS ACKNOWLEDGEMENTS _ i TABLE OF CONTENTS _ iii SUMMARY viii LIST OF TABLES _x LIST OF FIGURES xiv LIST OF ABBREVIATIONS xx LIST OF PUBLICATIONS xxiii LIST OF CONFERENCES _xxv CHAPTER INTRODUCTION 1.1 Significance 1.2 Literature Review 1.2.1 DNA Damage and Repair: linking ageing, cancer and developmental defects 1.2.2 Role of Reactive Oxygen Species in DNA damage 1.2.2.1 Arsenite and Oxidative Stress _ 1.2.2.2 Hydrogen Peroxide and Oxidative Stress 1.2.3 Role of NER in maintaining genome stability _ 1.2.4 The eukaryotic NER mechanism _ 10 1.2.5 Syndromes associated with NER defects _ 15 1.2.5.1 XPA, XPD and Xeroderma Pigmentosum _ 15 1.2.5.2 CSB and Cockayne Syndrome _ 17 1.2.5.3 Trichothiodystrophy 19 1.2.6 1.2.6.1 Ageing and Senescence 19 The Theories of Senescence _ 20 1.2.6.1.1 The mitochondrial free radical theory of ageing _ 20 1.2.6.1.2 Calorie Restriction _ 22 1.2.6.1.3 Telomeres and Cellular Senescence _ 23 1.2.6.1.4 DNA Repair Defects and Ageing 28 1.2.6.1.5 Genetics and the specificity of Premature and Natural Ageing 31 iii 1.2.6.2 1.3 The complex network process of ageing 34 Motivation and Direction: Linking NER factors to oxidative stress management of the genome and at the telomeres 36 1.4 Objectives _ 38 CHAPTER _ 39 MATERIALS AND METHODS _ 39 2.1 Cells and cell culture conditions 39 2.1.1 Human diploid fibroblasts _ 39 2.1.2 Human B-lymphoblastoids 39 2.2 Cells treatment conditions 40 2.2.1 Arsenite treatment conditions 40 2.2.2 Hydrogen Peroxide (H2O2) treatment conditions _ 40 2.3 Cell Viability Assays _ 41 2.3.1 Cell Viability Assay for adherent cells by Crystal Violet 41 2.3.2 Cell Viability Assay for suspension cells by MTT _ 41 2.4 Analysis of cell cycle by Fluorescence Activated Cell Sorting (FACS) 42 2.5 DNA Damage Markers _ 43 2.5.1 Cytokinesis Blocked Micronucleus (CBMN) analysis 43 2.5.2 Peptide Nucleic Acid-Fluorescence in-situ hybridisation (PNA- FISH) for chromosome aberration (CA) analysis _ 44 2.5.3 2.6 Alkaline single cell gel electrophoresis (SCGE/Comet) assay _ 45 Gene Expression Studies _ 46 2.6.1 RNA extraction _ 46 2.6.2 RNA quantification and qualification _ 46 2.6.3 Gene Expression Studies/Arrays _ 47 2.6.3.1 Oligo GEArray Human Apoptosis Microarray Analysis _ 47 2.6.3.2 Microarray Gene Chip Analysis _ 48 2.6.4 Real Time RT-Polymerase Chain Reaction (PCR) 50 2.7 Protein Expression Studies 53 2.8 Long Term Study _ 54 2.8.1 Cells and treatment 54 2.8.2 Population doubling (PD) _ 54 2.8.3 Morphology by light microscopy 55 2.8.4 Senescence Associated ß-Galactosidase (SA-ß gal) Staining _ 55 2.8.5 Cell Size 56 iv 2.8.6 Telomere Length measurement by Terminal Restriction Fragment (TRF) _ _ 56 2.9 Statistical Analysis 57 CHAPTER _ 58 Role of Xeroderma Pigmentosum A (XPA) protein in genome maintenance in human cells under oxidative stress _ 58 3.1 Background 58 3.2 Objectives _ 60 3.3 Results _ 61 3.3.1 Oxidative stress decreases cell viability, with XPA-deficient cells showing less sensitivity 61 3.3.2 XP-A fibroblasts display G1 and S phase arrest at a lower dose as compared to Normal fibroblasts after As3+ treatment 63 3.3.3 XP-A fibroblasts retain G2/M arrest following H2O2 treatment _ 63 3.3.4 XPA-L lymphoblastoids not display obvious changes in cell cycle profiles following H2O2 treatment _ 64 3.3.5 XPA-deficient cells display significantly more DNA damage than control cells following oxidative damage _ 68 3.3.5.1 Cytokinesis-blocked micronucleus assay _ 68 3.3.5.2 Chromosome Aberration assay _ 73 3.3.6 Lack of XPA function results in compromised capacity to repair oxidative DNA lesions 77 3.3.7 Differential apoptosis-related gene and protein expression patterns in XPA-deficient and Normal fibroblasts following As3+ treatment using Superarray _ 83 3.3.8 Differential gene expression patterns in XPA-deficient and Normal fibroblasts following arsenite and H2O2 treatment using Microarray _ 89 3.3.9 Fibroblasts exhibit senescent features earlier when subjected to oxidative stress, with XP-A fibroblasts showing accelerated signs of senescence compared to Normal fibroblasts 95 3.3.10 3.4 XP-A fibroblasts are more sensitive to telomere attrition _ 97 Discussion _ 106 CHAPTER 120 Role of Xeroderma Pigmentosum D (XPD) protein in genome maintenance in human cells under oxidative stress 120 4.1 Background _ 120 4.2 Objectives 123 v 4.3 Results 124 4.3.1 H2O2 treatment decreases cell viability, with XPD-deficient fibroblasts showing less sensitivity but XPD-deficient lymphoblastoids showing more sensitivity _ 124 4.3.2 XP-D fibroblasts display minimal morphological changes following H2O2 treatment 124 4.3.3 XP-D fibroblasts not display cell cycle profile changes following H2O2 treatment 127 4.3.4 XPD-L lymphoblastoids are more sensitive to H2O2 treatment- induced cell death 128 4.3.5 XPD-deficient cells display significantly more DNA damage than control cells following H2O2 treatment 134 4.3.5.1 Cytokinesis-blocked micronucleus assay 134 4.3.5.2 Chromosome Aberration assay 138 4.3.6 Lack of functional XPD increases DNA damage susceptibility and compromises oxidative DNA lesion-repair _ 141 4.3.7 Fibroblasts exhibit senescent features earlier when subjected to oxidative stress, with XP-D fibroblasts showing accelerated signs of senescence compared to control fibroblasts _ 144 4.3.7.1 Chronic treatment using 10 µM H2O2 results in reduced PDN, morphology changes indicative of senescence and accelerated telomere shortening, where XP-D cells exhibit senescent characteristics earlier and increased telomere attrition _ 146 4.3.7.2 Chronic treatment using 20 µM H2O2 and 40 % O2 accelerated features of senescence and telomere shortening, where XP-D cells exhibit senescent characteristics earlier and increased telomere attrition _151 4.3.8 Differential gene expression patterns in XPD-deficient and Normal fibroblasts following H2O2 treatment using microarray analysis _ 163 4.4 Discussion _ 167 CHAPTER 179 Role of Cockayne Syndrome B (CSB) protein in genome maintenance in human cells under oxidative stress 179 5.1 Background _ 179 5.2 Objectives 181 5.3 Results 182 vi 5.3.1 H2O2 treatment decreases cell viability of cells with CSB-deficient fibroblasts showing less sensitivity _ 182 5.3.2 CS-B fibroblasts display minimal morphological changes following H2O2 treatment 182 5.3.3 CS-B fibroblasts showed signs of late S-phase arrest following H2O2 –treatment _ 182 5.3.4 CS-B cells produced significantly more micronuclei than Normal cells following H2O2 treatment 190 5.3.5 Lack of functional CSB increases DNA damage susceptibility to H2O2 and compromises H2O2-induced DNA lesion-repair _ 194 5.3.6 Fibroblasts exhibit senescent features earlier when subjected to oxidative stress, with CS-B fibroblasts showing accelerated signs of senescence compared to control fibroblasts _ 195 5.3.6.1 Chronic exposure to 10 µM H2O2 results in reduced PDN, morphology changes indicative of senescence and accelerated telomere shortening, where CS-B cells exhibits earlier senescent characteristics and increased telomere attrition _ 195 5.3.6.2 Chronic treatment using 20 µM H2O2 and 40 % O2 accelerated features of senescence and telomere shortening, where CS-B cells exhibit senescent characteristics earlier and increased telomere attrition 202 5.3.7 Differential gene expression patterns in CSB-deficient and Normal fibroblasts following H2O2 treatment _ 214 5.4 Discussion _ 217 CHAPTER 227 Conclusion _ 227 6.1 Comparing between the loss of XPA, XPD and CSB _ 227 6.2 Limitations and future directions _ 227 6.3 Final remarks _ 230 CHAPTER 235 Bibliography 235 vii SUMMARY The role of nucleotide excision repair (NER) in the maintenance of DNA integrity under oxidative assault has yet to be elucidated A defective NER can result in Xeroderma Pigmentosa (XP) or Cockayne Syndrome (CS), both autosomal recessive diseases, presenting with increased cancer risk and segmental progeria Although the NER is characterized to be involved in repairing UV-induced damage, it is difficult to attribute all the symptoms of XP and CS to UV-damage Oxidative stress is thus likely to be an important factor Other DNA repair proteins including a component of the NER pathway, XPF, have been reported to be involved in telomere dynamics As the importance of the NER pathway in removing oxidative stress-induced DNA lesions is still unclear, we sought to understand the role of NER in oxidative stress-induced damage protection and telomere-mediated chromosome integrity In our study, we utilized primary cells derived from patients suffering from XP (XP-A and XP-D) and CS Type II (CS-B), as well as transformed lymphoblastoid cells from XP-A and XP-D patients The XPA protein verifies DNA damage sites, an event integral for the recruitment of downstream factors such as XPD which is a helicase domaincontaining protein involved in both the NER and basal transcription CSB, which displaces stalled RNA polymerase II, is involved in restoring UV-inhibited transcription and basal transcription Dysfunction of any of these proteins impedes the progression of the NER Following induction of oxidative stress by either sodium arsenite (NaAsO2) or hydrogen peroxide (H2O2), we performed assays related to survival, genome stability and growth kinetics NER-deficient primary fibroblasts retained higher viability but displayed cell cycle dysfunction and increased DNA damage following exposure to viii H2O2 Single cell gel electrophoresis assay showed that both fibroblasts and lymphoblastoids deficient in NER were more susceptible to H2O2-induced DNA damage and retained more damage following recovery Cells lacking functional NER also 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Gopalakrishnan K, Sethu S, Manikandan J, Hande MP Role of DNA repair factors in telomere integrity and genome maintenance in mammalian cells under oxidative stress International Congress on Cell Biology,... 53:45-48 Low GKM, Hande MP 2008 Role of DNA Repair Factors in Telomere Integrity and Genome Maintenance in Mammalian Cells Under Oxidative Stress Cell Biology – International Congress on Cell