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THE HERPES SIMPLEX VIRUS VIRION HOST SHUTOFF PROTEIN IS TARGETED to Mrna CLEAVAGE SITES THROUGH INTERACTIONS with COMPONENTS O

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THE HERPES SIMPLEX VIRUS VIRION HOST SHUTOFF PROTEIN IS TARGETED TO mRNA CLEAVAGE SITES THROUGH INTERACTIONS WITH COMPONENTS OF THE HOST TRANSLATIONAL APPARATUS A DISSERTATION IN Cell Biology and Biophysics and Molecular Biology and Biochemistry Presented to the Faculty of the University of Missouri-Kansas City in partial fulfillment of the requirements for the degree DOCTOR OF PHILOSOPHY by LORA ANN SHIFLETT M.S., University of Missouri-Kansas City, Kansas City, MO 2007 B.S., Iowa State University, Ames, Iowa, 2005 Kansas City, MO 2010 ©2010 LORA ANN SHIFLETT ALL RIGHTS RESERVED THE HERPES SIMPLEX VIRUS VIRION HOST SHUTOFF PROTEIN IS TARGETED TO mRNA CLEAVAGE SITES THROUGH INTERACTIONS WITH COMPONENTS OF THE HOST TRANSLATIONAL APPARATUS Lora Ann Shiflett, Candidate for the Doctor of Philosophy Degree University of Missouri-Kansas City, 2010 ABSTRACT The virion host shutoff protein (Vhs) is a herpes simplex virus (HSV) protein involved in early shutoff of the host cell. It is a component of the infecting virion, located in the tegument region, that works by rapidly degrading both viral and cellular messenger RNA (mRNA). in vivo and within infected cells, Vhs is selective for degrading messenger RNA opposed to non- messenger RNA. This dissertation sought to examine Vhs cleavage of an mRNA that utilizes the cap-dependent scanning mechanism for translation initiation and to see if cleavage was connected to early events of translation initiation. mRNA encoding HSV-1 thymidine kinase (pBK2) was used for the majority of the experiments, and studies were designed to map the cut sites produced by Vhs in a rabbit reticulocyte lysate (RRL) system. Additional experiments investigated whether Vhs was selective for degrading certain types of mRNAs over others, particularly IRES-containing mRNAs. Studies revealed that Vhs specifically cleaves pBK2 mRNA within the first 300 bases from the 5’ cap, and these cut sites are close to and slightly upstream from the first three AUG codons of the sequence. The proximity of the cutting to the AUG codons led to speculations that early events of translation initiation might be involved in Vhs degradation of mRNA. This was found to be true, where data revealed that blocking early stages such as (1) recruitment of ii translation initiation factors to the 5’ cap and/or (2) ATP hydrolysis RNA helicase activity important for unwinding RNA secondary structure and the scanning process hinder Vhs cleavage. However, blocking later stages of translation initiation only had a modest effect on RNase activity. Results also found that a 5’ cap analog inhibits Vhs site-specific cleavage of mRNA at regions near the 5’ cap. Interestingly, a cap appears to be required for Vhs production of specific cleavage sites within the first 300 bases of the transcript. Work went on to study whether there was a difference between Vhs cleavage of circularized RNA that normally experiences cap-dependent scanning and circularized RNA that initiates translation in a cap-independent manner. Results indicated that Vhs requires a free 5’ end for specific cleavage of mRNA that undergoes cap-dependent scanning. However, Vhs does not require a free 5’ end to specifically cleave a circular RNA that utilizes cap-independent methods for translation initiation. Mutational work, with pBK2 mutants which contained mutations in or surrounding the AUG codon, further supported a mechanism for Vhs cleavage that involved Vhs association with the scanning complex to reach some of its preferred cut sites. Mutating the first AUG to a non-AUG inhibited Vhs specific cleavage of pBK2 mRNA at a region just upstream from the AUG codon. Additionally, mutating bases surrounding the AUG codon to put it in an optimal context enhanced cleavage at regions near the start codon. Inserting a stable hairpin near the 5’ cap to block scanning also reduced Vhs cleavage at prominent sites within the first 300 bases of the transcript. To conclude, this work provides several indications that Vhs associates with components of the translational apparatus to access at least some of its cut sites. iii APPROVAL PAGE The faculty listed below, appointed by the Dean of the School of Graduate Studies, have examined a dissertation titled “The Herpes Simplex Virus Virion Host Shutoff Protein is Targeted to mRNA Cleavage Sites through Interactions with Components of the Host Translational Apparatus,” presented by Lora Ann Shiflett, candidate for the Doctor of Philosophy degree, and certify that in their opinion it is worthy of acceptance. SUPERVISORY COMMITTEE G. Sullivan Read, Ph.D., Committee Chair Cell Biology and Biophysics Thomas Menees, Ph.D. Cell Biology and Biophysics Michael Plamann, Ph.D. Cell Biology and Biophysics Stephen King, Ph.D. Molecular Biology and Biochemistry Michael O'Connor, Ph.D. Molecular Biology and Biochemistry iv CONTENTS ABSTRACT .............................................................................................................................................. ii APPROVAL PAGE ................................................................................................................................ iv LIST OF ILLUSTRATIONS ................................................................................................................... vi LIST OF TABLES .................................................................................................................................... ix AKNOWLEDGEMENTS ........................................................................................................................ x Chapter 1. INTRODUCTION .............................................................................................................................. 1 2. MATERIALS AND METHODS ..................................................................................................... 27 3. RESULTS ........................................................................................................................................... 68 4. DISCUSSION .................................................................................................................................. 138 REFERENCES ...................................................................................................................................... 155 VITA .................................................................................................................................................. 173 v ILLUSTRATIONS Figure Page 1. HSV Virion Components ................................................................................................................. 4 2. Cap-meditated Translation Initiation ........................................................................................... 17 3. Viral Internal Ribosome Entry Sites ............................................................................................... 21 4. Cartoon Depiction of Bicistronic Construct .................................................................................. 29 5. Vhs Assay Procedure with Internally-labeled mRNA Substrate ............................................... 40 6. Vhs Assay Procedure for Cap-labeled or Poly(A) Tail-labeled mRNA..................................... 42 7. Vhs Assay Procedure from Inhibition Studies with Cap-labeled mRNA ................................. 44 8. Vhs Assay Procedure for Analysis of Vhs Cleavage of Circular vs. Linear pBK2 mRNA ..... 53 9. Procedure for Mutating AUG Codons ........................................................................................... 56 10. Nucleotide Sequence Constructed by IDT Technologies and Inserted into a pIDTSMART Mini Gene ............................................................ 60 11. RNA Structures ............................................................................................................................... 63 12. Outline of Plasmid Combinations ................................................................................................ 65 13. Synthesis of Vhs Protein in a Rabbit Reticulocyte Lysate System ............................................ 71 14. Vhs Degradation of Internally Labeled pBK2 RNA ................................................................... 72 15. Vhs Degradation of Cap-labeled vs. Tail-labeled RNA ............................................................. 73 16. Analysis of Smaller pBK2 RNA Cleavage Products .................................................................. 75 17. Degradation of pBK2 mRNA Using Serial Two Fold Dilutions of Vhs Protein ..................... 77 18. mRNA Cut Site Analysis After Using *α-32P]GTP with a Higher Specific Activity .............. 78 19. Mapping pBK2 Cut Sites with 5’ Cap Labeling .......................................................................... 80 20. Vhs Assay with pBK2 mRNA Using Extended Time Points .................................................... 81 vi 21. Primer Extension Analysis of pBK2 mRNA Cut Sites ...................................................................... 83 22. Mapping pBK2 Cut Sites Using Primer Extension Analysis ............................................................ 84 23. Summary of the Prominent Cut Sites Identified through 5’ Cap-labeling and Primer Extension Analysis .................................................... 86 24. Vhs Degradation of mRNA in the Presence of Cycloheximide ....................................................... 88 25. Vhs Site Specific Cleavage of mRNA in the Presence of Cycloheximide
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