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Protein-Protein Interactions of Bacterial Topoisomerase I Srikanth Banda [email protected]

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Protein-Protein Interactions of Bacterial Topoisomerase I Srikanth Banda Sband003@Fiu.Edu Florida International University FIU Digital Commons FIU Electronic Theses and Dissertations University Graduate School 6-29-2017 Protein-protein Interactions of Bacterial Topoisomerase I Srikanth Banda [email protected] DOI: 10.25148/etd.FIDC001958 Follow this and additional works at: https://digitalcommons.fiu.edu/etd Part of the Bacteriology Commons, Biochemistry Commons, Biotechnology Commons, Microbial Physiology Commons, Molecular Biology Commons, and the Other Biochemistry, Biophysics, and Structural Biology Commons Recommended Citation Banda, Srikanth, "Protein-protein Interactions of Bacterial Topoisomerase I" (2017). FIU Electronic Theses and Dissertations. 3378. https://digitalcommons.fiu.edu/etd/3378 This work is brought to you for free and open access by the University Graduate School at FIU Digital Commons. It has been accepted for inclusion in FIU Electronic Theses and Dissertations by an authorized administrator of FIU Digital Commons. For more information, please contact [email protected]. FLORIDA INTERNATIONAL UNIVERSITY Miami, Florida PROTEIN-PROTEIN INTERACTIONS OF BACTERIAL TOPOISOMERASE I A dissertation submitted in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in BIOCHEMISTRY by Srikanth Banda 2017 To: Dean Michael R. Heithaus College of Arts, Sciences and Education This dissertation, written by Srikanth Banda, and entitled Protein-protein Interactions of Bacterial Topoisomerase I, having been approved in respect to style and intellectual content, is referred to you for judgment. We have read this dissertation and recommend that it be approved. _______________________________________ Yesim Darici _______________________________________ Yuan Liu _______________________________________ Xiaotang Wang _______________________________________ Watson Lees _______________________________________ Yuk-Ching Tse-Dinh, Major Professor Date of Defense: June 29, 2017 The dissertation of Srikanth Banda is approved. _______________________________________ Dean Michael R. Heithaus ol College of Arts, Sciences and Education _______________________________________ Andrés G. Gil Vice President for Research and Economic Development and Dean of the University Graduate School Florida International University, 2017 ii © Copyright 2017 by Srikanth Banda All rights reserved. iii DEDICATION I dedicate this dissertation to my mother, and my wife, for their unconditional love and support. iv ACKNOWLEDGMENTS I’m grateful to all the people at FIU, for without their support and encouragement, I would not be able to accomplish much of my work. I’m forever indebted to my advisor, Dr. Yuk-Ching Tse-Dinh, for her constant support and advice. I have learnt a lot from her mentorship, and I’m grateful to have worked under her guidance. I would like to thank my committee members, Dr. Watson Lees, Dr. Xiaotang Wang, Dr. Yesim Darici and Dr. Yuan Liu, for their guidance and support throughout my Ph.D. training. I would also like to thank Dr. Prem Chapagain, Dr. Jin He, Dr. Xuewen Wang for their guidance. I would like to thank Dr. Purushottam Babu Tiwari for his help with the SPR experiments. I would like to thank all my peers, and lab members for their support and advise in my research. I would like to thank Dr. Arasu Annamalai for patiently advising and guiding me in the lab. I would like to thank Qingxuan Zhou, Nan Cao, Pamela Gracia Moreno, Shayna Sandhaus, Wenjie Wang, Jose Chang, Angelo Andres, as well as other past and present lab members for their help and support. I’m grateful for the Research assistantship provided by FIU College of Arts, Sciences and Education through the School of Integrated Science and Humanity (SISH). v ABSTRACT OF THE DISSERTATION PROTEIN-PROTEIN INTERACTIONS OF BACTERIAL TOPOISOMERASE I by Srikanth Banda Florida International University, 2017 Miami, Florida Professor Yuk-Ching Tse-Dinh, Major Professor Protein-protein interactions (PPIs) are essential features of cellular processes including DNA replication, transcription, translation, recombination, and repair. In my study, the protein interactions of bacterial DNA topoisomerase I, an essential enzyme, were investigated. The topoisomerase I in bacteria relaxes excess negative supercoiling on DNA, and maintains genomic stability. Investigating the PPI network of DNA topoisomerase I can further our understanding of the various functional roles of this enzyme. My study is focused on topoisomerase I of Escherichia coli and Mycobacterium smegmatis. Firstly, we have explored the biochemical mechanisms for an interaction between RNA Polymerase, and topoisomerase I in E. coli. Molecular docking, and molecular dynamic simulations have predicted that the interactions are mediated through electrostatic, and hydrogen bonding. The predicted Lysine residues (K627, K664) of topoisomerase I that are involved in the electrostatic interactions were mutated to Alanine, and its effect on the binding efficiency with RNA polymerase was reported. In a separate study, PPI partners of topoisomerase I in mycobacteria were identified. Knowledge gained from the study can provide valuable insights into the physiological functions of a validated drug target, DNA topoisomerase I, in pathogenic mycobacteria. Co-immunoprecipitation, and pull-down vi assays were coupled to mass spectrometry for identification of the protein partners of mycobacterial topoisomerase I. The study has identified RNA polymerase, and putative helicases (DEAD/DEAH BOX helicases) as potential protein partners of mycobacterial topoisomerase I. My results indicated that the tail region of the CTD-topoisomerase I was required for direct physical interaction with the RNAP beta’ subunit. My studies have also verified the physiological relevance of the topoisomerase I - RNA polymerase interactions for survival under antibiotic, and oxidative stress. Lastly, I report a direct physical interaction between E. coli topoisomerase I and RecA by pull-down assays. Previous studies have shown that RecA, a DNA repair protein, can stimulate the relaxation activity of E. coli topoisomerase I. Our new results showed that the stimulatory effect can be attributed to the physical interaction of topoisomerase I with RecA. vii TABLE OF CONTENTS CHAPTER PAGE INTRODUCTION ...............................................................................................................1 A. TOPOISOMERASES AND GENOME STABILITY ...................................................1 B. TOPOISOMERASES AS THERAPEUTIC TARGETS………………………………9 C. PROTEIN-PROTEIN INTERACTIONS; CROSS-TALK BETWEEN PROTEINS ...19 D. BACTERIAL TOPOISOMERASE I…………………………………………………26 OVERVIEW ......................................................................................................................30 CHAPTER 1: MOLECULAR MECHANISMS OF INTERACTION BETWEEN E. COLI RNA POLYMERASE AND TOPOISOMERASE I ..........................................32 ABSTRACT .......................................................................................................................32 INTRODUCTION .............................................................................................................33 MATERIALS AND METHODS .......................................................................................35 RESULTS AND DISCUSSION ........................................................................................41 CONCLUSIONS ...............................................................................................................44 CHAPTER 2: IDENTIFICATION OF PROTEIN PARTNERS OF MYCOBACTERIAL TOPOISOMERASE I .....................................................................49 ABSTRACT .......................................................................................................................49 INTRODUCTION .............................................................................................................50 MATERIALS AND METHODS. ......................................................................................54 RESULTS………………………………………………………………………………..60 DISCUSSION ....................................................................................................................71 CHAPTER 3: EVOLUTION OF A NOVEL MECHANISM FOR MYCOBACTERIAL RNA POLYMERASE AND TOPOISOMERASE I INTERACTION ............................74 ABSTRACT .......................................................................................................................74 INTRODUCTION .............................................................................................................75 MATERIALS AND METHODS .......................................................................................76 RESULTS ..........................................................................................................................90 DISCUSSION ..................................................................................................................104 CHAPTER 4: INVESTIGATING A DIRECT INTERACTION BETWEEN ESCHERICHIA COLI TOPOISOMERASE I AND RECA ............................................107 ABSTRACT .....................................................................................................................107 INTRODUCTION ...........................................................................................................107 MATERIALS AND METHODS .....................................................................................111 RESULTS ........................................................................................................................117
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