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The Functional Role of NRAP in the Nucleolus

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The Functional Role of NRAP in the Nucleolus The Functional Role of NRAP in the Nucleolus Author Inder, Kerry Published 2006 Thesis Type Thesis (PhD Doctorate) School School of Biomolecular and Biomedical Sciences DOI https://doi.org/10.25904/1912/3452 Copyright Statement The author owns the copyright in this thesis, unless stated otherwise. Downloaded from http://hdl.handle.net/10072/367738 Griffith Research Online https://research-repository.griffith.edu.au THE FUNCTIONAL ROLE OF NRAP IN THE NUCLEOLUS Presented by Kerry Inder, B Biomed Sci. (Hons) A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy School of Biomolecular and Biomedical Science And Natural Product Discovery Faculty of Science, Griffith University, Brisbane, Australia Submitted March, 2006 I STATEMENT OF ORIGINALITY The material presented in this thesis has not previously been submitted for a degree in any university. To the best of my knowledge and belief, the thesis contains no material previously published or written by another person except where due reference is made in the thesis itself. Kerry Inder. II PUBLICATIONS AND ABSTRACTS ARISING FROM THIS STUDY PUBLICATIONS Inder, K.L., Utama, B., Gan, Y., Wang, X., and Kennedy, D. Nrap/Nol6 is involved in rRNA processing through the regulation of B23/NPM and p19ARF. (submitted) ABSTRACTS Inder, K.L., Utama, B., Gan, Y., Wang, X., and Kennedy, D. Nrap/Nol6 is involved in rRNA processing through the regulation of B23/NPM and p19ARF., ComBio Combined Conference, Adelaide, Australia, 2005. (oral presentation) Hartmann, B., Aitken, K.L., Utama, B., Kennedy, D. Nrap, a novel nucleolar protein which interacts with B23/Nucleophosmin during ribosome biogenesis. East Coast Protein Meeting, Coffs Harbour, Australia, 2003. III ACKNOWLEDGEMENTS For the opportunity to undertake my PhD and the financial support to complete it, I must thank Ron Quinn from Natural Product Discovery, Griffith University. I must also mention Rama Addepalli and Sandra Duffy (also of Natural Product Discovery) for their encouragement to commence my PhD and support, both scientific and emotional throughout. To all the staff and students in the school of Biomolecular and Biomedical Science at Griffith University, I also give my sincere thanks. Of these, special mention must be made to fellow students Jamie Nourse and Emily Dunner for their endless advice. Also, I acknowledge my supervisor Derek Kennedy and all the past and previous members of the RNA Metabolism Laboratory for their support. A special mention must go to Belinda Hartmann for her scientific advice, but more importantly her support and friendship through the fluctuations of a PhD. This advice extended beyond her time as part of the RNA Metabolism group and I wish her all the best in her knew found direction. I also thank Matthew Walker Brown, for endless patience while working with me through the most taxing times. Finally, of the RNA Metabolism Laboratory students, I would like to thank Renee Stirling. Renee provided me with endless advice towards my study. Renee deserves thanks for her patience and understanding in some of the most difficult times. To Associate Professor Xing Li Wang, and all the members of his laboratory at the Department of Molecular Virology and Microbiology, Division of Cardiothoracic Surgery, Baylor College of Medicine, Houston, Texas, USA, my sincere thanks. Your support was very much appreciated and surpassed any expectations one could hope for. The time in this laboratory renewed my enthusiasm for research, and gave me the self- confidence and drive needed to achieve my objectives. Most of all I must acknowledge Budi Utama, research officer at Baylor College of Medicine. His interest and enthusiasm towards my research was greatly appreciated but most of all I am grateful for his scientific advice which continued after leaving Texas and well into the final stages of my studies. His advice and assistance was imperative in the completion of my PhD and extended beyond that of a friend or colleague to the level of mentor. IV I would like to thank Dr Charles Sherr, St. Judes Children’s Research Hospital, Tennessee, USA, for providing the p19ARF construct used as a template in this project. Also to Kienan Savage, Queensland Institute of Medical Research, who kindly donated some anti-p53 antibody. In addition, I thank all those colleagues I have failed to mention but in some way have assisted with protocols and reagents. Finally I wish to acknowledge all my friends and family who have supported me throughout my PhD. My biggest thanks go to my husband, Shannon. Your patience, love and understanding did not go unnoticed. V ABSTRACT The nucleolus is the site for rRNA synthesis, a process requiring the recruitment of many proteins involved in ribosomal biogenesis. Nrap is a novel nucleolar protein found to be present in all eukaryotes. Preliminary characterisation of Nrap suggested it was likely to participate in ribosome biogenesis but as with many other nucleolar proteins, the functional role of Nrap is largely unknown. In this study, the role of mammalian Nrap in the nucleolus and in ribosome biogenesis was explored. Initially, a number of tools were generated to investigate Nrap function. This involved raising and purifying a polyclonal antibody against the N-terminal region of Nrap. The anti-Nrap antibody was found to detect two Nrap bands in mouse fibroblast cells, possibly corresponding to the two mouse Nrap isoforms, α and β. In addition, mammalian expression vectors containing the full Nrap sequence as well as deletion constructs were created. The subcellular localisation of each construct was observed by fluorescent microscopy. It was revealed that recombinant Nrap did not localise to the nucleolus, possibly because it was exported to undergo degradation by the 26S proteasome. Two putative NLSs were found to be responsible for directing Nrap to the nucleus but a region accountable for nucleolar localisation was not identified. The data indicated that multiple domains working together are likely to direct Nrap to the nucleolus. Nrap was also observed to co-localise with nucleolar proteins B23 and p19ARF. Moreover, it was shown by reciprocal immunoprecipitation that these three nucleolar proteins existed in a complex in unsynchronised mouse fibroblast cells. Recent reports demonstrated a complex relationship between B23 and p19ARF although the functional significance remained unclear. Nrap’s in vivo association with B23 and p19ARF indicated a specific functional role in the nucleolus. Nrap knockdown using siRNA significantly increased B23 protein levels in a dose-dependent manner and down- regulated p19ARF protein levels at higher siRNA concentration. Preliminary studies also implicated Nrap in cell proliferation through these novel interactions. Both endogenous and recombinant Nrap were found to be highly unstable suggesting that Nrap might regulate B23 and p19ARF through its own tightly regulated stability. VI Finally, the role of Nrap in rRNA processing was investigated by northern blot analysis. Nrap knockdown was found to affect the levels of 45S, 32S and 28S rRNAs. The changes found may be a consequence of the concurrent perturbation in the levels of B23 and p19ARF caused by Nrap knockdown. As the results were not consistent with previous reports, it was likely that changes to rRNA processing could be contributed to Nrap loss of function. This study demonstrated for the first time a functional role of Nrap in rRNA processing possibly through its association with B23 and p19ARF. VII TABLE OF CONTENTS Title ..................................................................................................................... I Statement of Originality ....................................................................................... II Publications and Abstracts Arising from this Study............................................. III Acknowledgements .............................................................................................. IV Abstract................................................................................................................. VI Table of Contents ................................................................................................. VIII List of Figures....................................................................................................... XIII List of Tables........................................................................................................ XV List of Abbreviations............................................................................................ XVI CHAPTER ONE: General Introduction......................................................... 1 1.1 INTRODUCTION................................................................................ 2 1.2 Nucleolus.......................................................................................... 3 1.3 Nucleolus During Mitosis ................................................................ 4 1.4 rDNA Transcription ......................................................................... 5 1.5 rRNA Processing and Assembly ...................................................... 8 1.6 snoRNAs and snoRNPs.................................................................... 10 1.7 Nucleolar Proteins ............................................................................ 11 1.8 Nuclear and Nucleolar Transport ..................................................... 14 1.9 Emerging Nucleolar Functions........................................................
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