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Ribosome Maturation in Yeast Models of Diamond-Blackfan Anemia and Shwachman-Diamond Syndrome

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Ribosome Maturation in Yeast Models of Diamond-Blackfan Anemia and Shwachman-Diamond Syndrome University of Louisville ThinkIR: The University of Louisville's Institutional Repository Electronic Theses and Dissertations 5-2010 Ribosome maturation in yeast models of Diamond-Blackfan anemia and Shwachman-Diamond syndrome. Joseph Brady Moore 1981- University of Louisville Follow this and additional works at: https://ir.library.louisville.edu/etd Recommended Citation Moore, Joseph Brady 1981-, "Ribosome maturation in yeast models of Diamond-Blackfan anemia and Shwachman-Diamond syndrome." (2010). Electronic Theses and Dissertations. Paper 1002. https://doi.org/10.18297/etd/1002 This Doctoral Dissertation is brought to you for free and open access by ThinkIR: The University of Louisville's Institutional Repository. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of ThinkIR: The University of Louisville's Institutional Repository. This title appears here courtesy of the author, who has retained all other copyrights. For more information, please contact [email protected]. RIBOSOME MATURATION IN YEAST MODELS OF DIAMOND-BLACKFAN ANEMIA AND SHWACHMAN-DIAMOND SYNDROME By Joseph Brady Moore IV B.S., University of Louisville, 2005 M.S., University of Louisville, 2009 A Dissertation Submitted to the Faculty of the Graduate School of the University of Louisville in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Department of Biochemistry and Molecular Biology University of Louisville Louisville, Kentucky May 2010 Copyright 2010 by Joseph B. Moore IV All rights reserved RIBOSOME MATURATION IN YEAST MODELS OF DIAMOND-BLACKFAN ANEMIA AND SHWACHMAN-DIAMOND SYNDROME By Joseph Brady Moore IV B.S., University of Louisville, 2005 M.S., University of Loiusville, 2009 A Dissertation Approved on April 12,2010 by the following Dissertation Committee: Dissertation Director: Dr. Steve Ellis Dr. Nancy Martin Dr. Johnson Liu Dr. Yong Li Dr. Tom Geoghegan ii DEDICATION This dissertation is dedicated to my father Mr. Joseph Brady Moore III who provided me with the determination, the courage, and the opportunities to become the person I am today. Sine labore nihil. iii ACKNOWLEDGEMENTS First, I would like to thank my mentor and friend, Dr. Steven R. Ellis, for his unwavering support and guidance throughout my graduate career. His unique style of teaching and scholarly approach to science has left a lasting impression that will forever have a positive influence on me as a scientific investigator and as a future mentor. I would also like to thank my committee members, Dr. Tom Geoghegan, Dr. Johnson Liu, Dr. Yong Li, and Dr. Nancy Martin for their helpful suggestions and technical support throughout my dissertation project. I extend a special thanks to Dr. William Dean for his friendship, encouragement, direction, and professional scientific advice throughout the years when I was at my absolute worst and best ... you are truly a lifelong friend and a wealth of knowledge. Additionally, I express thanks to Dr. Michael Flaherty for his friendship, intriguing scientific discussions, pep talks, and advice. Dr. Flaherty's ambition and true love of medicine, science, and research inspired me to work harder and smarter than ever before. What is more, Dr. Flaherty motivated me not only to meet expectations, but also to exceed them ... thank you so much for your help. I would also like to show appreciation to Dr. Larry Bozulic for his years of camaraderie and instruction during my time as a graduate student. Further, I express gratitude to my friends, colleagues, parents, and family for their support, especially Kathy Moore, whose unfaltering care, love, and encouragement throughout the years had a profound influence on my development as an individual. iv Lastly, I would like to thank the Biochemistry Department, for affording me the opportunity to pursue this degree, and to all of its faculty members, as each contributed in some way to my growth as a scientist. Thank you all! v ABSTRACT RIBOSOME MATURATION IN YEAST MODELS OF DIAMOND-BLACKFAN ANEMIA AND SHW ACHMAN-DIAMOND SYNDROME Joseph B. Moore IV April 12, 2010 The inherited bone marrow failure syndromes (IBMFS) encompass a heterogeneous collection of rare disorders characterized by hematological abnormalities, generalized growth delays, and an increased incidence of malignant transformation. These disorders include: Diamond-Blackfan anemia (DBA), Shwachman-Diamond syndrome (SDS), cartilage-hair hypoplasia (CHH), and dyskeratosis congenita (DC). Despite sharing overarching similarities, each of these disorders manifests distinct clinical phenotypes. Similar to their clinical features, the molecular underpinnings of the IBMFS have characteristics that are both shared and distinctive. Aberrations in ribosome synthesis have been associated with each of the IBMFS providing a common molecular target for pathogenic mutations in disease related genes. In some cases, the ribosome appears to be the major target of pathogenic lesions, whereas in others, effects on ribosome synthesis are secondary and appear to have a modifying influence on disease presentation. For example, the primary target of pathogenic lesions in dyskeratosis congenita is telomerase which distinguishes it from other IBMFS. The X-linked form of dyskeratosis congenita, however, affects both telomerase function and ribosome synthesis and is considerably more severe than the somatic forms of the disease that only affect vi telomerase. Thus, differences in primary targets of pathogenic lesions can account for the distinct clinical presentations of certain mMFS. In other cases, where ribosome synthesis appears to be the major target of disease causing mutations, the basis for diverse clinical manifestations remains unknown. The body of work presented in this dissertation is focused on Shwachman­ Diamond syndrome and Diamond-Blackfan anemia, two mMFS where defects in ribosome synthesis appear to underlie disease pathophysiology. The approach was to use yeast models of both diseases to explore mechanisms by which ribosome synthesis was affected using the 60S ribosomal subunit as a common molecular target. My studies revealed that 60S subunit biogenesis was affected by distinct mechanisms in the two disease models and that these differences may provide the molecular underpinnings for the distinct clinical presentations observed in DBA and SDS patients. Further studies on the mechanism by which 60S subunit biogenesis was affected in the SDS model have clear implications for the treatment of this disorder. vii TABLE OF CONTENTS PAGE DEDICATION .................................................................................... iii ACKNOWLEDGEMENTS .................................................................... .iv ABSTRACT ....................................................................................... vi LIST OF FIGURES .............................................................................. x CHAPTER I: FROM RIBOSOMES TO MARROW FAILURE ................................... l General Introduction ............................................................ 1 The Cell's Translational Machinery .......................................... 2 Diamond-Blackfan Anemia .................................................... 17 Shwachman-Diamond Syndrome ............................................. 24 Dissertation Overview ......................................................... 34 II: DISTINCT RIBOSOME MATURATION DEFECTS IN YEAST MODELS OF DIAMOND-BLACKFAN ANEMIA AND SHWACHMAN-DIAMOND SYNDROME. ....................................... 36 Introduction ..................................................................... 36 Design and Methods ............................................................ 39 Results ........................................................................... 43 Discussion ....................................................................... 56 viii III: THE SBDS FAMILY OF PROTEINS REGULATE 60S SUBUNIT MATURATION BY MODULATING PROTEIN ACETyLATION ............ 64 Introduction ..................................................................... 64 Design and Methods ............................................................ 67 Results ........................................................................... 72 Discussion ....................................................................... 90 IV: CONCLUDING REMARKS .......................................................... 99 REFERENCES .................................................................................... 106 APPENDICES ..................................................................................... 122 CURRICULUM VITAE ......................................................................... 147 ix LIST OF FIGURES PAGE FIGURE 1. Ribosome maturation in E. coli and S. cerevisiae .................................... 7 2. Saccharomyces cerevisiae rRNA processing ......................................... 11 3. Ribbon diagram modeled after the crystal structure of the Methanothermobacter thermautotrophicus SBDS protein (mthSBDS) .......... 28 4. Haploid yeast strains possessing deletions in RPL33A or SDO 1 have a pronounced growth defect. ............................................................. .44 5. Yeast models of DBA and SDS both exhibit deficits in the relative amount of 60S to 40S ribosomal subunits ............................................ .45 6. Yeast models of DBA and SDS display discrete pre-rRNA processing defects ....................................................................................
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