Regulation of DNA (cytosine 5) methyltransferase 1 in the cell cycle and its role(s) in doxorubicin mediated micronuclei formation

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Regulation of DNA (cytosine 5) methyltransferase 1 in the cell cycle and its role(s) in doxorubicin mediated micronuclei formation

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REGULATION OF DNA (CYTOSINE-5) METHYLTRANSFERASE IN THE CELL CYCLE AND ITS ROLE(S) IN DOXORUBICIN-MEDIATED MICRONUCLEI FORMATION TAN HWEE HONG NATIONAL UNIVERSITY OF SINGAPORE 2008 REGULATION OF DNA (CYTOSINE-5) METHYLTRANSFERASE IN THE CELL CYCLE AND ITS ROLE(S) IN DOXORUBICIN-MEDIATED MICRONUCLEI FORMATION TAN HWEE HONG (B.Sc, Murdoch University) A THESIS SUBMITTED FOR THE DEGREE OF DOCTORATE OF PHILOSOPHY INSTITUTE OF MOLECULAR AND CELL BIOLOGY AND DEPARTMENT OF PHYSIOLOGY NATIONAL UNIVERSITY OF SINGAPORE 2008 ACKNOWLEDGEMENTS I would like to thank my supervisor, Associate Professor Benjamin F.L.Li, for having faith in my ability to undertake graduate studies and for his guidance and encouragement throughout the years I would also like to thank Professor Alan Porter, Associate Professor Cai Mingjie and Dr Linda Chuang, members of my supervisory committee, for their advice and discussion I would like to extend my sincere appreciation to; Prof Alan Porter for his willingness to guide me through the last year of my PhD I am most grateful to him for giving me constructive suggestions for my project, and for reading and editing my thesis I really appreciate his constant encouragement A/Prof Manoor Prakash Hande for his kindness in helping me cross the final hurdle Dr Linda Chuang for teaching me many useful techniques and for sharing with me her invaluable knowledge on DNA methylation I am grateful for her guidance and her friendship all these years To Miss Yeo Wanlin and Dr Vinay Badal for their friendship and encouragement To Dr Oh Hue Kian and Miss Swa Li Foon for their collaborations Members of Prof Porter’s laboratory for sharing their knowledge in cell death Special thanks to my husband for his support and understanding throughout the years Finally, I would like to dedicate this thesis with great love to my parents and my husband, without whom none of this would have been possible i SUMMARY DNA methyltransferase (DNMT1) is the major methyltransferase involved in maintenance methylation of newly synthesized DNA The regulation of DNMT1 expression is critical in coordinating DNMT1 activity with biological processes and therefore must be tightly regulated in the cell cycle Interestingly, DNMT1 expression is inversely correlated with the cell cycle inhibitor p21WAF1 protein in mammalian cells, which is independent of the tumor suppresser p53 as shown here Using a combination of experimental protocols including cell synchronization studies, transient over-expression, siRNA-mediated depletion and luciferase reporter assays, the roles of the transcription factors E2F1 and Sp1, and the transcriptional coactivator p300 in the regulation of DNMT1 expression were investigated Transcription from the human DNMT1 promoter was shown to be dependent on E2F1 and Sp1 In addition, this study has identified p300 as a crucial transcriptional coactivator for E2F1 and Sp1 in regulating DNMT1 expression Most importantly, this report demonstrates for the first time that p21WAF1 negatively regulates DNMT1 at the transcriptional level The up-regulation of p21WAF1 by in-vitro over-expression or by treatment with Trichostatin A led to the corresponding down-regulation of DNMT1, which consistently coincided with the reduction of p300 Although p21WAF1 is known to inhibit the transcriptional activity of E2F1, my data show that p21WAF1 may potentially inhibit p300, either directly or indirectly Surprisingly, DNMT1 was down-regulated by TSA treatment in the absence of p300, which may be due to the selective depletion of Sp1 that only occurs when p300 is absent Nevertheless, my findings provide the outline of a mechanistic explanation for the inverse relationship between DNMT1 and p21WAF1 in mammalian cells This novel p21WAF1-E2F1/p300- ii DNMT1 pathway may play a pivotal role to ensure regulated DNMT1 expression and DNA methylation in mammalian cell division De-regulated DNMT1 expression is often associated with tumorigenesis, and there are reports suggesting that DNMT1 acts as a potential target for cancer therapy I attempted to compare the genotoxic effects of doxorubicin, a Topoisomerase II poison commonly used in chemotherapeutic treatments, on normal and cancer human cell lines, and the potential involvement of DNMT1 in this doxorubicin-induced cytotoxicity The physiological significance of the relationship between p300 and DNMT1 was further highlighted in the doxorubicin-mediated DNA damage response, which consistently depleted p300, and consequently DNMT1, in non-tumorigenic but not tumorigenic cells My data further show that doxorubicin selectively induces micronucleation preceded by senescence-like morphological changes in transformed or tumorigenic cells only, and this consistently correlates with a decrease in cell viability and an increase in cell death Importantly, I discovered for the first time a positive link between DNMT1 protein expression and micronuclei formation However, although I provide strong evidence that DNMT1 plays a significant role in doxorubicin-induced micronucleation, which may lead to cellular demise; it remains unclear to what extent DNMT1 contributes to the ultimate cell death Nevertheless, my findings strongly support DNMT1 as one molecular target for doxorubicininduced cytotoxicity in mammalian cancer cells I proposed that the expression levels of DNMT1 in tumor cells may potentially determine the effectiveness of doxorubicin in chemotherapy This novel observation enhances the understanding of drug response during doxorubicin administration in cancer therapy iii TABLE OF CONTENTS Acknowledgements i Summary ii Table of Contents iv List of Tables ix List of Diagrams ix List of Figures x Abbreviations xiv Chapter 1: 1.1 INTRODUCTION Historical Overview of DNA Methylation 1.1.1 1.1.2 DNA methylation in eukaryotic cells Mammalian DNA methylation 1.1.3 Demethylation of 5MeC 1.1.4 1.2 DNA methylation in prokaryotic cells Host defense versus DNA methylation Mammalian DNA Methyltransferases 1.2.1 DNMT1 DNMT1 variants 1.2.2 10 1.2.3 DNMT3a and DNMT3b 11 1.2.4 1.3 DNMT2 Cooperation among the DNMTs 12 Roles of DNA Methylation 1.3.1 Genomic imprinting 13 1.3.2 X-chromosome inactivation 15 1.3.3 Epigenetic regulation of genes 16 1.3.3a DNMT1 interacts with G9a histone methylase 17 1.3.3b DNMT1 interacts with Polycomb Group (PcG) proteins 17 1.3.3c DNMT1 interacts with UHRF1 18 Transcriptional suppression 19 1.3.4 iv 1.4 DNMT1 in the Cell Cycle 1.4.1 21 1.4.2 E2F1/RB pathway 23 1.4.3 p300/CBP co-activator 25 1.4.4 DNMT1 and DNA replication 27 1.4.5 DNMT1 and PCNA 27 1.4.6 1.5 Regulation of DNMT1 expression DNMT1 and p21WAF1 29 Regulation of p21WAF1 Expression 1.5.1 p53-dependent trancriptional regulation of p21WAF1 WAF1 31 1.5.2 31 1.5.3 1.6 p53-independent transcriptional regulation of p21 Translational regulation of p21WAF1 32 DNA Damage Response 1.6.1 33 1.6.2 Cell cycle checkpoints 34 1.6.3 DNMT1 and p53 36 1.6.4 DNMT1 in DNA damage and repair 37 1.6.5 1.7 ATM/ATR signaling pathways The nucleolus – a DNA damage response center 38 Micronuclei 1.7.1 40 1.7.2 DNMT1 and micronuclei 41 1.7.3 Possible DNA content in the micronuclei 42 1.7.4 1.8 Micronuclei - What are they? Doxorubicin 43 Research Objectives Chapter 2: 45 MATERIAL AND METHODS 2.1 Mammalian cell cultures 47 2.2 Antibodies 47 2.3 Bacterial strain 48 2.4 Drugs and Chemicals 48 2.5 Drug treatments 48 2.6 Harvesting of mammalian cells 48 2.7 Flow cytometry analysis 49 2.8 Cell viability and cell proliferation assays 49 v 2.9 Lactate Dehydrogenase (LDH) cell death assay 49 2.10 Purification of total RNA 50 2.11 Reverse transcription and PCR 50 2.12 Purification of genomic DNA 51 2.13 DNA agarose gel electrophoresis 52 2.14 Methylation-sensitive McrBc restriction digestion 52 2.15 Cell lysis 52 2.16 Western blot analysis 53 2.17 DNA manipulations 54 2.18 Mammalian expression plasmids 54 2.19 Cloning of full length DNMT1 into pXJ40-Flag vector 56 2.20 Cloning of DNMT1 promoter construct into pGL3-Basic vector 56 2.21 Preparation of competent cells 57 2.22 Transfection 58 2.23 Luciferase reporter assay 58 2.24 siRNA experiments 59 2.25 Cell staining 60 2.26 Cell count for micronuclei frequency 60 2.27 Comet assay 61 Chapter 3: 3.1 RESULTS AND DISCUSSION Regulation of DNMT1 expression in the Cell Cycle 3.1.1 Inverse relationship between DNMT1 and p21WAF1 in the 63 cell cycle 3.1.1.1 3.1.1.2 DNMT1 expression in the cell cycle 63 WAF1 in DNA 67 p21WAF1 68 Transient over-expression of DNMT1 does not inhibit 71 Inverse relationship between DNMT1 and p21 damage 3.1.1.3 Inverse relationship between DNMT1 and expression is independent of p53 3.1.1.4 p21WAF1 3.1.1.5 siRNA-mediated depletion of DNMT1 does not induce 72 p21WAF1 vi 3.1.1.6 Transient over-expression of p21WAF1 inhibits DNMT1 73 3.1.1.7 TSA-mediated induction of p21WAF1 results in inhibition of 76 DNMT1 3.1.1.8 TSA-mediated induction of p21WAF1 is independent of p53 85 3.1.2 Transcriptional regulation of human DNMT1 promoter 89 3.1.2.1 siRNA-mediated depletion of E2F1 results in down- 89 regulation of DNMT1 3.1.2.2 siRNA-mediated depletion of p300 results in down- 92 regulation of DNMT1 3.1.2.3 Transcriptional regulation of DNMT1 promoter by E2F1, 97 Sp1 and p300 3.1.3 3.2 Discussion 101 The Role(s) of DNMT1 in Doxorubicin-mediated micronuclei formation 3.2.1 Doxorubicin mediates selective depletion of DNMT1 in non- 108 transformed cell lines 3.2.2 Doxorubicin induces micronuclei formation in transformed 112 cell lines 3.2.3 Doxorubicin-mediated micronuclei formation is a general 118 phenomenon in transformed cell lines 3.2.4 Doxorubicin retards proliferation in both transformed and 120 non-transformed cell lines 3.2.5 Doxorubicin induces micronuclei formation in transformed 124 cell lines in a dose and time-course dependent manners 3.2.6 Induction of micronuclei correlates with decrease in cell 125 viability and increase in cell death in the transformed cell lines 3.2.7 Doxorubicin-mediated micronuclei structures are sites of 129 DNA damage 3.2.8 Depletion of DNMT1 by 5AzadC treatment attenuates Dox- 132 mediated micronuclei formation vii 3.2.9 Knockout of DNMT1 attenuates Dox-mediated micronuclei 136 formation 3.2.10 Knockdown of DNMT1 by siRNA-mediated transfection 141 attenuates Dox-mediated micronuclei formation 3.2.11 Chapter 4: Discussion CONCLUSIONS, 144 IMPLICATIONS AND FUTURE DIRECTIONS Conclusions 151 Implications and Future Directions 154 Chapter 5: REFERENCES 164 Chapter 6: APPENDIX List of Publications 190 viii Klisovic RB, Stock W, Cataland S, Klisovic MI, Liu S, Blum W et al (2008) A phase I biological study of MG98, an oligodeoxynucleotide antisense to DNA methyltransferase 1, in patients with high-risk myelodysplasia and acute myeloid leukemia Clin Cancer Res 14: 2444-9 Korba BE, Hays JB (1982) Novel mutations of Escherichia coli that produce recombinogenic lesions in DNA V Recombinogenic plasmids from arl mutants of Escherichia coli are unusually sensitive to nuclease S1 and partially deficient in cytosine methylation at C-C-(A/T)-G-G sequences J Mol Biol 157: 213-35 Kottke TJ, Blajeski AL, Meng XW, Svingen PA, Ruchaud S, Mesner PW, Jr et al (2002) Lack of 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and p21WAF1 in the 63 cell cycle 3 .1. 1 .1 3 .1. 1.2 DNMT1 expression in the cell cycle 63 WAF1 in DNA 67 p21WAF1 68 Transient over-expression of DNMT1 does not inhibit 71 Inverse relationship... methylase 17 1. 3.3b DNMT1 interacts with Polycomb Group (PcG) proteins 17 1. 3.3c DNMT1 interacts with UHRF1 18 Transcriptional suppression 19 1. 3.4 iv 1. 4 DNMT1 in the Cell Cycle 1. 4 .1 21 1.4.2 E2F1/RB

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