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Dna Replication IDENTIFICATION OF PUTATIVE FUNCTIONAL MOTIFS IN VIRAL PROTEINS ESSENTIAL FOR HUMAN CYTOMEGALOVIRUS (HCMV) DNA REPLICATION Heng Giap Woon Master of Science (Research) 2008 ABSTRACT Human cytomegalovirus (HCMV) is a ubiquitous virus that causes significant morbidity and mortality in immunocompromised individuals. Although there are prophylactic treatments available, all current antiviral drugs ultimately target the DNA polymerase, resulting in the increasing emergence of antiviral resistant strains in the clinical setting. There is a fundamental need for understanding the role of other essential genes in DNA replication as a foundation for developing new antiviral treatments that are safe and which utilize a mechanism of action different to existing therapies. In this study we looked at six HCMV replication genes encoding for the DNA polymerase accessory protein (UL44), single stranded DNA binding protein (UL57), primase (UL70), helicase (UL105), primase-helicase associated protein (UL102), and the putative initiator protein (UL84) in order to increase our understanding of their role in DNA replication. The aim of this project was to identify variation within these genes as well as to predict putative domains and motifs in order to ultimately express and study the functional properties of the HCMV primase (UL70) through the use of recombinant mutants. Sequencing of these genes revealed a high degree of conservation between the isolates with amino acid sequence identity of >97% for all genes. Using ScanProsite software from the Expert Protein Analysis System (ExPASy) proteomics server, we have mapped putative motifs throughout these HCMV replication genes. In particular, highly conserved putative N- linked glycosylation sites were identified in UL105 that were also conserved across 33 homologues as well as several unique motifs including casein kinase II phosphorylation sites (CKII) in UL105 and UL84, a microbodies signal motif in UL57 and an integrin binding site in the UL102 helicase-primase associated protein. Our investigations have also elucidated motif-rich regions of the UL44 DNA polymerase accessory protein, mapped functionally important domains of the UL105 helicase and identified cysteine motifs that have implications for folding of the UL70 primase. Taken together, these findings provide insights to regions of these HCMV replication proteins that are important for post-translation modification, activation and overall function, and this information can be utilized to target further research into these proteins and advance the development of novel antiviral agents that target these processes. I ACKNOWLEDGEMENTS I would like to thank my supervisor, Dr Gillian Scott, for her guidance and encouragement throughout the project, and to my co-supervisor, Professor Bill Rawlinson, for his advice and for giving me the opportunity to work in research. I would also like to extend my thanks to Professor Andrew Lloyd for his advice and guidance. I would also like to thank my colleagues at the Virology Research Lab for their company, friendship, encouragement, advice and humor. In particular, thanks to Sharon and Min for the countless conversations over lunch. Thanks to the people at the UNSW Ramaciotti Centre for their technical aid in this project. I would like to give a special thanks to Professor Patrick Tam for his insights and advice on science research in general and to my parents who have supported me throughout. Finally I would like to give a very special thanks to Ying, who kept me company on the long nights in the lab and while writing this thesis. II TABLE OF CONTENTS ABSTRACT………………………………………………………………………….....I ACKNOWLEDGEMENTS………………………………………………………......II TABLE OF CONTENTS…………………………………………………………….III LIST OF TABLES…………………………………………………………………....VI LIST OF FIGURES……………………………………………………………….....VII COMMONLY USED ABBREVIATIONS………………………………………..VIII 1 INTRODUCTION............................................................................................... 1 1.1 BIOLOGY....................................................................................................... 1 1.1.1 The herpesviridae .................................................................................. 1 1.1.2 The Cytomegaloviruses.......................................................................... 2 1.2 HCMV EPIDEMIOLOGY................................................................................ 3 1.2.1 Transmission ......................................................................................... 4 1.2.2 Congenital infection............................................................................... 5 1.2.3 Immunocompromised infection and disease outcomes............................ 6 1.2.4 Antiviral treatment................................................................................. 6 1.2.5 Antiviral resistance................................................................................ 8 1.3 HCMV GENOME STRUCTURE AND ORGANIZATION..................................... 13 1.3.1 Open reading frame organization ........................................................ 13 1.4 CMV GROWTH CYCLE ................................................................................ 14 1.4.1 Cell attachment and viral entry............................................................ 15 1.4.2 HCMV replication genes...................................................................... 16 1.4.3 DNA replication................................................................................... 24 1.4.4 Capsid assembly, maturation and egress.............................................. 25 1.4.5 Latency and reactivation...................................................................... 26 1.5 AIMS AND OBJECTIVES ............................................................................... 26 III 2 REAGENTS AND EQUIPMENT .................................................................... 28 2.1 VIRAL STOCKS ............................................................................................ 28 2.2 DNA EXTRACTION ...................................................................................... 28 2.2.1 Buffers................................................................................................. 28 2.2.2 Chenicals............................................................................................. 28 2.2.3 Kits...................................................................................................... 29 2.3 POLYMERASE CHAIN REACTION (PCR) ...................................................... 29 2.3.1 Buffers................................................................................................. 29 2.3.2 Enzymes............................................................................................... 29 2.3.3 Equipment ........................................................................................... 30 2.3.4 Reagents.............................................................................................. 30 2.4 ELECTROPHORESIS ..................................................................................... 30 2.4.1 Buffers................................................................................................. 30 2.4.2 DNA Markers ...................................................................................... 31 2.4.3 Equipment ........................................................................................... 31 2.4.4 Reagents.............................................................................................. 31 2.5 DNA SEQUENCING ...................................................................................... 32 2.5.1 Equipment ........................................................................................... 32 2.5.2 Reagents.............................................................................................. 32 2.6 RESTRICTION ENZYMES .............................................................................. 32 2.6.1 Buffers................................................................................................. 32 2.6.2 Enzymes............................................................................................... 33 2.6.3 Reagents.............................................................................................. 33 2.7 CLONING REAGENTS ................................................................................... 33 2.7.1 Antibiotics ........................................................................................... 33 2.7.2 Cells .................................................................................................... 34 2.7.3 Equipment ........................................................................................... 34 2.7.4 Kits...................................................................................................... 35 2.7.5 Media .................................................................................................. 36 2.7.6 Reagents.............................................................................................. 36 2.7.7 Vectors ................................................................................................ 36 2.8 PROTEIN EXPRESSION AND DETECTION....................................................... 37 2.8.1 Antibodies............................................................................................ 37 IV 2.8.2 Buffers................................................................................................
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