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Identifying Subunit Organization and Function of the Nuclear RNA Exosome Machinery The Texas Medical Center Library DigitalCommons@TMC The University of Texas MD Anderson Cancer Center UTHealth Graduate School of The University of Texas MD Anderson Cancer Biomedical Sciences Dissertations and Theses Center UTHealth Graduate School of (Open Access) Biomedical Sciences 5-2018 Identifying Subunit Organization and Function of the Nuclear RNA Exosome Machinery Jillian Losh Follow this and additional works at: https://digitalcommons.library.tmc.edu/utgsbs_dissertations Part of the Medicine and Health Sciences Commons Recommended Citation Losh, Jillian, "Identifying Subunit Organization and Function of the Nuclear RNA Exosome Machinery" (2018). The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access). 835. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/835 This Dissertation (PhD) is brought to you for free and open access by the The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences at DigitalCommons@TMC. It has been accepted for inclusion in The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access) by an authorized administrator of DigitalCommons@TMC. For more information, please contact [email protected]. IDENTIFYING SUBUNIT ORGANIZATION AND FUNCTION OF THE NUCLEAR RNA EXOSOME MACHINERY by Jillian Strother Losh, A.S., B.S. IDENTIFYING SUBUNIT ORGANIZATION AND FUNCTION OF THE NUCLEAR RNA EXOSOME MACHINERY A DISSERTATION Presented to the Faculty of The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY by Jillian Strother Losh, A.S., B.S. Houston, TX May 2018 DEDICATION This work is dedicated to my father, Daniel Strother Losh. Dad, thank you for consistently supporting me in all of my endeavors, big and small. As I enter the professional world, I hope to model what you have done: achieve an extremely successful career, while constantly maintaining the balance between work, family, and self-acceptance. I love you and I am proud to share my accomplishments with you. iii ACKNOWLEDGEMENTS First and foremost, thank you to Ambro van Hoof, my mentor. I am so grateful that you have always respected my career goals and cheered my pursuit of them. You have encouraged me to have fun and given me emotional support during the moments where there was no fun at all. You have constantly pushed me to improve my skills and allowed me to fully take ownership of my work, while being a patient advisor and my friend. I would like to thank Anita Corbett, Milo Fasken, and their laboratory at Emory University for a wonderful partnership on our PCH1b work. This was my first foray into formal science collaboration and it was a fantastic experience. I am glad that we have developed this project, as well as friendships. Thank you to Sean Johnson and his laboratory at Utah State University for assistance with fluorescence anisotropy analysis of TRAMP complex subunits. Thank you to the members of my Advisory Committee: Danielle Garsin, Eric Wagner, Kevin Morano, and Michael Lorenz for your continued guidance and encouragement. Thank you to the two additional members of my Qualifying Exam Committee: Nayun Kim and Heidi Kaplan. I am extremely appreciative to have had faculty members on both of these committees, as well as in my classes, who are such a motivating force. Also, thank you to those of you who have provided me with the use of equipment, reagents, and other materials. I would also especially like to thank Eric Solberg and Stephen Linder for providing me with opportunities to learn more about science policy and for pushing me to exercise that knowledge. Special thanks to Danielle Garsin for welcoming me into her lab as an undergraduate student in 2011. Danielle, as well as Garsin Lab members Katie McCallum, Liz Gendel, Ransom van der Hoeven, and Sruti DebRoy, introduced me to graduate school and encouraged me to pursue a Ph.D., even when I was not iv yet sure of myself. Thank you to my undergraduate faculty at University of Houston-Downtown, especially Akif Uzman, Poonam Gulati, and Lisa Morano. I would also like to give very special acknowledgment to the Morano family. In addition to Kevin’s guidance throughout graduate school, Lisa was the first person to ever tell me that I should consider pursuing a Ph.D. degree. You are both my role-models as researchers, advisors, and all-around wonderful humans. I would like to thank the GSBS Deans and staff for their support of my academic and extracurricular pursuits on campus. Thank you to GSBS, the R.W. Butcher family, GSEC, and Dean Barbara Stoll of McGovern Medical School for granting me awards during graduate school that have been so beneficial to my growth as a scientist. Additional thanks to the MMG/MID staff, especially Lyz Culpepper and Chris McKenzie, for all of your help with student-related and science-related matters. I am so very fortunate to have joined MMG/MID, a wonderfully close-knit group of faculty, students, technicians, and staff with a strong passion for learning, collaboration, and Halloween costumes. Thank you to all of my wonderful GSBS friends, especially: Kara Schoenemann for being my personal stand-up comedian and a pretty swell gal, Sara Peffer for the Netflix/PBS binging and to-do-list mastering, Doug Litwin for the gossiping, Jennifer Abrams for the dancing, Aundrietta Duncan and Kimiya Mermarzadeh for starting and continuing our wonderful GSA Officer family, and Alex Perakis for the continuous partnership in global domination. Thank you to all of the past and present members of the van Hoof Lab, especially to Ale King for her initial guidance into both my thesis project and working with yeast. Also, shout-out to my three undergraduate mentees, Alex Morano, Jillian Vaught, and Keta Patel. I am so happy to have been your “Science Big Sister” and am immensely proud of all three of you! I will be forever thankful to v my long-term labmates, Jaeil Han and Minseon Kim for their endless supply of friendship, positivity, and support (and cat babysitting) over the years. Also, I want to extend a warm welcome to the newest van Hoovian, Jennifer Hurtig. I am happy and excited to leave the future of my project in your hands! To Alex Marshall, my best friend and true soul sister: I am glad to have earned this degree, but I am equally glad to have gotten to sit back-to-back with you for 1 million years while we figured out how to get through grad school. I would do it with you for 100 million more years if the lab wasn’t so cold. Thank you to my father, Dan Losh, for just honestly being the best dad in the universe. Thank you to Uncle Richard, Aunt Carol, and my stepmom Becky for your sincere love and joy whenever I succeed at something. Thank you to my pets, Hooligan and Bubba, for keeping me humble and covered in fur. Gracias a toda mi familia Peruana, especialmente a Nora y William Ojeda, quienes me han apoyado, amado, y considerado una hija desde el comienzo. To my husband, Matthew: Thank you for the constant encouragement, the fun, the food, and the unconditional love. I love you. vi IDENTIFYING SUBUNIT ORGANIZATION AND FUNCTION OF THE NUCLEAR RNA EXOSOME MACHINERY Jillian Strother Losh, A.S., B.S. Advisory Professor: Ambro van Hoof, Ph.D. The eukaryotic RNA exosome processes and degrades many classes of RNA. It is present in the nucleus and the cytoplasm, highly evolutionarily conserved, and essential for viability. Since the RNA exosome is such a significant component of the RNA degradation machinery, it is unsurprising that even single point mutations in a few of its subunits have been linked to human disease. For example, at least eight point mutations in a single subunit of the RNA exosome have been linked to pontocerebellar hypoplasia subtype 1b (PCH1b). My work has included the development of a laboratory model system to assess the specific effects of these mutations on the structure and function of the RNA exosome. My collaborators and I have employed the common model organism Saccharomyces cerevisiae for this work since both the RNA exosome and other components of RNA degradation machinery are conserved throughout eukaryotes. Our research has shown that at least one PCH1b-associated mutation negatively affects the stability of the RNA exosome, although it remains functional. The effect of this mutation is conserved between yeast and mouse cells. The RNA exosome requires various cofactors in both the nucleus and the cytoplasm for substrate delivery. The other half of my work focuses on a nuclear cofactor of the RNA exosome, the TRAMP complex. This complex is comprised of an RNA helicase and a poly(A) polymerase, as well as an RNA-binding subunit. However, it is currently unclear how the TRAMP complex is specifically assembled and moreover, if it is essential for life. The poly(A) polymerase subunit consists of a catalytic domain, as well as disordered regions that vii are required for protein interactions. My work has shown that the catalytic core of the TRAMP complex is necessary and sufficient for its essential functions, although a specific interaction between the two enzymatic subunits is required for snoRNA biogenesis and possibly other cellular functions. These and future studies will help define the role of the TRAMP complex in the RNA degradation process and determine its importance for cellular viability.
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