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Downloaded from Uniprot on 2/15/13, 20,259 Protein Sequence Entries) UCSF UC San Francisco Electronic Theses and Dissertations Title Role of Post-Translational Protein Modifications in Regulating HIV-1 and Mammalian Transcription Permalink https://escholarship.org/uc/item/39r6d242 Author Ali, Ibraheem Irfan Publication Date 2018 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California i ii Dedication I want to dedicate this thesis to my mother, my family and those that give me inspiration. I first need to thank Irfan Ayub Ali, my dad. The summer before this all started mom, Monica Lourido-Ali, passed away after her 10 year battle with cancer. I want to thank you for everything you have been through these last few years. I know navigating the challenges and changes in our lives has been really hard for you, but I will always admire the peace and philosophies you bring to the spaces we share. Seeing you happy, active, and on what seems like a perpetual vacation (the photos of all your travels makes me a bit jealous :P), will continue to make me smile and roll my eyes. You are so cool. Thanks for being such an important part to the most interesting family in the world. I need to thank my cousins Adam, Alex, Emiliano, Igor, Marco and Eduardo and my siblings Ismail and Ishaq for their collective support during this period in my life. I’m glad that whenever I needed people to catch me, you were always there posting memes and being the ridiculous, ugly bunch of humans that you are. I am thankful for my Fresno family for your energy and passion towards life, and making sure that Fresno will still always feel like home. Especialmente quiero darle gracias a mi abuela Blanca Lourido, gracias por tu esfuerzo inmenso que necesitábamos para crear la familia que tenemos aquí en California. Siempre vivirás en mi corazón, te quiero y extraño mucho. My friends away from lab have played an important role in helping me feel like I’m doing something that matters in this world. Thank you Eleanor, Darlene, Yulin, Isabel, Eric, Olav, Rahul, Mariska, Wesley, Nayely, Jeff, Matt, Belle, Stephanie, Ariane, Shri, Darby, Cindy, Jacob, Aida, Abdallah and Matthew; you each helped breathe life into me at critical points in my life when I needed it most. I’m thankful for the community that I found here at UCSF. Especially Aaron, Christy, Andrew, Kat, Tim, Yvanka, Roman, Lindsey, Tommy, Dan, KT, Ali, Sumitra, Jhia, Kojo, Francesca, Aude, Joe, Stephanie, Devin, Andrew, John and Eric. Thanks Donna for iii your support and the valuable lessons you taught me as I navigated this life. Everyone here has played an important role in my wellbeing and growth. I appreciate your presence and patience working, living, and being with me; it is been quite the ride. I also need to thank all the mentors, faculty and staff I had at UCSF who helped me work on projects outside the lab that gave me inspiration. For helping me with curriculum development, mentorship and mental health projects I want to thank Dr. Marc Ansel, Dr. Anita Sil, Dr. Doug Gould, Dr. Liz Silva, Dr. D’Anne Duncan, Dr. Liz Watkins, Dr. Jeanne Stanford, Dr. Alexandra Thurston, Demian Sainz, Ned Molyneaux and Lisa McGargal. For projects with the library and scholarly communication I want to thank Annelise Taylor, Kemi Amin, Jim Munson, Dr. Russ Cucina, Dr. Rich Schneider, Daniella Lowenberg, Dr. Marielle Cavrois. Finally I must thank my lab family which has gone through many renditions, all of which were necessary for helping want to come back to the lab and keep doing the challenging work that is scientific research. Thank you Daniela, Gregory, Drew, Doro, Sebastian, Pao-Chen, Renu, Mark, Ryan, Ansu, Olivia, Chia-Lin, Krystal, Parinaz, Kris, Irene, Albert, Jen &Sakshi. This document and all of my successes I dedicate to you all. iv Acknowledgements I am immensely grateful for all the mentorship and support that I received which allowed me to produce this body of work. First and foremost I am grateful for the support of Dr. Melanie Ott. She has been instrumental in driving my academic and personal growth by putting many opportunities and challenges in my way and believing in me when I needed to trust my instincts in science. I want to thank her for giving me the autonomy and flexibility to pursue my interests outside the lab and defending me when necessary. I want to thank Dr. JJ Miranda for his patience and care. You always kept my interests in mind when we talked and I am glad I could have a thesis committee chair I could trust to advocate for me when I was not sure how to advocate for myself. You are an incredible mentor and I was sad to see you leave UCSF. I would like to thank Dr. Bassem Al-Sady for your inspiring energy and always communicating science in a way that I could understand and be excited about. Also for being one of the coolest chromatin biologists I have ever met. You are an inspiration. I would also like to thank Dr. Holly Ramage. Your mentorship helped me build the foundation upon which I became an independent scientist, and helped teach me how to be a mentor to the various students I interacted with throughout my time at UCSF. This body of work would not have been possible without the help of many collaborators at UCSF and beyond. I want to thank all of the co-authors to the work that I have put into this document especially Mark Jeng, Ryan Conrad, Daniella Boehm, Pao-Chen Li, Zuyao Ni, Diego Garrido-Ruiz, Jeffrey Johnson, Katherine Aull, Naoki Sakane, Katrin Kaehlcke, Sara Pagans, Jinrong Min and Heng Zhang your experimental, writing and theoretical help have been essential for putting this work together. You are the reasons I can walk away feeling like a half decent scientist. I want to thank the other authors who provided advisory roles, reagents and laboratory infrastructure to create the environment necessary for these studies: Raymond Trievel, Martinal Schnoelzer, Masafumi Kamada, Robert Houz, Xinghua Guo, Matthew Jacobson, Jack Greenblatt, Eric Verdin and Nevan Krogan. v I want to thank the institutions that provided funding for my training including the NIH, but especially the American Society for Microbiology Robert D. Watkins Fellowship and the University of California, Discovery Fellowship for the funding and opportunities provided to me throughout my training. In this document I will provide a brief introduction and outline that will provide context for my studies in Chapter I, followed by the publications towards which I contributed substantially that are peer-reviewed literature reviews or original research in Chapters II-V. Followed by a chapter of conclusions and outlooks based on this body of work in Chapter VI. The citations for chapters II-V are as follows: Jeng M.Y., Ali I., Ott M. 2015. Manipulation of the host protein acetylation network by human immunodeficiency virus type-1. Crit. Rev. Biochem. Mol. Biol. 50, 314-325. Ali I., Ramage H., Boehm D. et al. 2016. The HIV-1 Tat Protein Is Monomethylated at Lysine 71 by the Lysine Methyltransferase KMT7. J Biol. Chem. 291, 16240-16248. Ali I., Conrad R.J., Verdin, E., Ott, M., 2018. Lysine Acetylation Goes Global: From Epigenetics to Metabolism and Therapeutics. Chem. Rev. 118 (3) 1216-1252. Ali I. et al. 2018 Crosstalk between RNA Pol II C-Terminal Domain Acetylation and Phosphorylation via RPRD Proteins. BioRxiv doi: https://doi.org/10.1101/442491 (Under Review, Molecular Cell) vi Role of Post-Translational Protein Modifications in Regulating HIV-1 and Mammalian Transcription Ibraheem Irfan Ali Abstract The molecular gatekeepers of nearly all gene expression in living cells are the proteins that function in the process of transcription. Transcription occurs when a cell must respond to a signal. These signals can be in the form of metabolic responses, signals for growth or differentiation, signals to defend against stress or pathogenic invasion, to name a few. The fundamentals of transcription have been extensively studied in bacterial systems and model organisms, but technical limitations have hindered their studies in mammalian and human systems. Recent developments in mass spectrometric methodologies, next-generation sequencing and techniques to study difficult-to-detect post-translational protein modifications are extensively reviewed here to highlight an important regulatory network through which gene expression is regulated. In addition, I present two vignettes: the first, a study of the regulatory mechanisms of monomethylation of the HIV-1 Tat protein in regulating HIV-1 gene expression and latency; the second, a study investigating the role of acetylation in regulating RNA Polymerase II protein modifications and gene expression in mammalian systems. Together, these studies combine new mass spectrometric techniques, modification-specific antibodies, protein purification methods, and next generation sequencing to better understand the role of these modifications in regulating the transcriptional response in mammalian systems. These findings can be applied to better understand mechanisms that regulate HIV-1 viral latency, along with fundamentally shifting the field of mammalian transcription by pinpointing unique modes of regulation only found in higher eukaryotes relevant to HIV-1 infection and cancer. vii Table of Contents Chapter I: Introduction ............................................................................................................ 1 DNA, RNA, Protein, Post-Translational Modification? ............................................................. 1 A Master of Immune Evasion .................................................................................................
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