Insights into the Regulation of Transcription Initiation of DNA Gyrase and Role of Transcription Factor Gre from Mycobacterium tuberculosis

Abstract

Genus Mycobacterium comprises a large number of species including many pathogens such as Mycobacterium leprae, Mycobacterium abscessus and Mycobacterium tuberculosis (Mtb), the last one is the causative agent of the fatal disease tuberculosis. The unique features of the deadly organism viz, slow growing, tough cell wall, latency and resistance to various drugs demand a systematic understanding of many essential molecular processes including transcription. Studies have been undertaken to understand several aspects of transcription in mycobacteria which revealed its machinery to be conserved with other eubacteria? However, many facets of transcription in mycobacteria and regulation are different. The transcription regulators and them regulation are the basic counter stones which govern gene expression. The present study is aimed to understand better the mechanistic regulation of transcription of important housekeeping functions, DNA gyrase and also to obtain further insights into the role of transcription elongation factor Gre. Chapter 1 of the thesis provides a general introduction of the bacterial transcription machinery, associated transcription regulators and their regulation. It covers the description of the central player- the RNA polymerase (RNAP) followed by each step of the transcription initiation, elongation and various factors involved in their regulation. Finally, an overview of the emerging information on several aspects of mycobacterial transcription is discussed emphasizing on RNAP, promoter architecture, and its regulation. In Chapter 2, the studies are directed to understand the mechanism for topology-dependent regulation of Mtb Gyrase. The gyrase is encoded by two genes gyrB and gyrA which form a bicistronicity operon in Mtb and harbor multiple promoters. The principal promoter PgyrB1 drives the transcription of the dicistron and the weaker divergent promoter PgyrR is engaged in transcription in the opposite direction. The divergent and overlapping PgyrR show decrease in activity when the Pgyr...