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Regulation of the ATR Pathway in the Replication Stress Response By Regulation of the ATR Pathway in the Replication Stress Response By Jessica Whitney Luzwick Dissertation Submitted to the Faculty of the Graduate School of Vanderbilt University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in Biochemistry August, 2016 Nashville, Tennessee Approved By David Cortez, Ph.D. Scott Hiebert, Ph.D. William Tansey, Ph.D. Jennifer Pietenpol, Ph.D. Stephen Fesik, Ph.D. To my husband and All those I have met along the way ACKNOWLEDGEMENTS This thesis is an accumulation of six years of struggle, accomplishments, disappointments, many highs and many lows. Every person I have meet along the way played some role in helping me complete this journey. I would like to thank my mentor, David Cortez for his guidance and wisdom through the years, for setting high standards, and for teaching me what it is to be a scientist. I would like to thank my committee members, Scott Hiebert, Jennifer Pietenpol, Bill Tansey, Steve Fesik, and Ellen Fanning for their advice and for sticking it out with me all these years. I am also appreciative of the funding I received from the Environmental Toxicology training grant. Throughout graduate school I had the benefit of working with awesome people every day. Even when the science was rough, the days long and stressful, I knew the people surrounding me would provide a reason to smile. The graduate students who came before me, Carol Bansbach, Edward Nam, Bianca Sirbu, and Jami Couch served as excellent mentors and role models. Carol and Eddie helped me to get started in the lab and set the bar high for being a graduate student in the Cortez lab. Bianca was a constant source of positivity and encouragement and Jami, the wise sage, was always so calm and confident. Gloria always keeps the lab stocked with both needed lab supplies and chocolate and who is constantly keeping things organized. Nancy became the CRISPR guru and made all the CRISPR cell lines and mutant ATR cell lines in this thesis. Clint, Gina, and Akosua all joined the lab around the same time I did. Clint was a constant source of enthusiasm that even though this experiment did not work, surely the next one would. Gina, the most experienced of the four of us, provided valuable wisdom iii and friendship. Akosua was my partner in crime as we navigated classes, quals, and committee meetings together. Huzefa, Kami, Lisa, and Kareem all joined the lab within the following couple years. Kareem convinced me to do the whole genome screen with him and while this resulted in a lot of struggle, I greatly benefited from his scientific guidance and friendship. Huzefa and Kami taught us all about India and very unfortunately, introduced the lab to going to Indian food for lunch. Kami and Lisa quickly became my friends and lab companions. We have had many adventures to concerts, movies, and other places creating many great memories from these years in Nashville. We have had a lot of laughs. Thomas was the latest graduate student to join the lab and fit right into our group. Maybe one day the lab will finally go canoeing. Finally, I would like to thank all the friends I have met in Nashville. My fellow IGPers with whom I started graduate school, Amanda Myer Johnson, Kate Mittendorf, and Liz Ferrick Kiddie. Liz and I interviewed at Vanderbilt the same weekend and was my first friend in Nashville. Amanda can always be counted on to have a smile on her face and to be enthusiastic about life. Kate, we have endured a lot together through these years and I will always treasure our friendship and being able to be truly me around you, no matter how sarcastic or blunt. There were many other friendships throughout the years and each provided a source of great memories. The friendships you have during graduate school are one of the greatest sources of encouragement and strength and without which, I would not have made it through this marathon of obtaining a Ph.D. I would like to thank my husband Tom. Who met me during my first year of graduate school and decided for whatever reason to stick it out with me. He never complained about the long hours, my moodiness, or silences when I would physically come iv home but mentally would still be back in lab. He became my rock and source of calm. I would like to thank my family for being understanding when I was not always pleasant or present and my sisters for having all the babies. During graduate school my four nieces and nephew were all born. Watching them grow provided perspective that whatever challenge I was currently facing was not all that big in the grand scheme of life and that human life, development from a single fertilized egg to a walking, talking 5-year-old with opinions, is truly a miracle. v TABLE OF CONTENTS Page DEDICATION .................................................................................................................... ii ACKNOWLEDGEMENTS ............................................................................................... iii LIST OF TABLES ...............................................................................................................x LIST OF FIGURES ........................................................................................................... xi LIST OF ABBREVIATIONS .......................................................................................... xiv CHAPTER I. INTRODUCTION .........................................................................................................1 The Cell Cycle and Checkpoints....................................................................................2 DNA Replication ...........................................................................................................4 Origin Licensing ......................................................................................................5 Origin Firing ............................................................................................................7 Regulation of Origins ...............................................................................................7 Regulation Fork Elongation .....................................................................................8 ATR and the Replication Stress Response.....................................................................8 Activation of ATR: RPA coated ssDNA gaps .........................................................9 Activation of ATR: ATR/ATRIP Complex ...........................................................11 Activation of ATR: 9-1-1 recruitment of TOPBP1 ...............................................12 Additional Components of the ATR Activation Pathway .....................................13 Alternative Mechanisms of ATR Activation .........................................................14 S-phase Checkpoint ...............................................................................................17 G2/M Checkpoint...................................................................................................21 Regulation of PIKK Kinases ........................................................................................23 Domain Architecture ..............................................................................................23 Regulation by Localization ....................................................................................26 Regulation by Protein Activators ...........................................................................28 Regulation by Post-translational Modifications.....................................................29 Targeting the DDR in Cancer ......................................................................................31 Oncogene Induced Replication Stress ...................................................................31 Inhibition of the DDR ............................................................................................32 ATR Inhibitors .......................................................................................................33 II. MATERIALS AND METHODS .................................................................................36 vi Site-directed Mutagenesis ............................................................................................36 Cell Lysate for Western Blot .......................................................................................38 Cell Lines .....................................................................................................................38 Transfection .................................................................................................................39 Reagents .......................................................................................................................40 ATR Kinase Assay .......................................................................................................40 Chromatin Fractionation ..............................................................................................42 Chromatin Fractionation: Alternative Method.............................................................43 DNA Fiber Labeling ....................................................................................................43 Flow Cytometry ...........................................................................................................45 Immunofluorescence ....................................................................................................46 Genetic Complementation of ATR Flox/-
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