Saravanan Matheshwaran

1. Dynamics of Chromatin Remodelling

The higher order organization of the chromatin governs and dictates the regulation of several cellular processes that deals with DNA. ATP-dependent chromatin remodeling complexes (CRCs) and modifying enzymes are important protein machineries that remodel or modify the higher order chromatin structure to sense and repair DNA damages. Chromatin constitutes a physical barrier to DNA repair machineries to reach the DNA. In order to deal with this impediment, transient chromatin structural changes are integral to different DNA repair pathways. The interactions between the DNA repair proteins and components of the CRCs, seems to be important for the regulation of DNA repair. However, the relation between CRCs and DNA repair proteins are not completely understood. Several studies show that INO80 CRC found in eukaryotes contains actin and several actin related proteins, play important roles in homologous recombination and DNA repair. Our laboratory is interested in examine the roles of Nuclear Actin and Actin Related Proteins (ARPs) in chromatin remodeling complex with the aim to understand their molecular mechanisms in chromatin targeting and remodeling. To fully understand the mechanism of action of chromatin remodeling complexes, it will be necessary to determine how their activities are regulated; how they are targeted to specific genes; how they interact with histone-modifying enzymes and other regulatory proteins to modulate chromatin. Our laboratory uses several model organisms such as, Saccharomyces cerevisiae, and  Ustilago maydis to address these important issues.

2. “SOS” response of Mycobacterium tuberculosis 

In response to continuous DNA damage, the bacterial cells employ specific DNA repair systems that help maintain genome integrity. The first response towards DNA damage is the induction of SOS response, which involves expression of several genes, which participate in a variety of DNA metabolic activities such as replication, repair, recombination and mutagenesis. Under normal growth conditions the SOS genes are expressed at a basal level, which increases distinctly upon induction of the SOS response in many bacterial species including Mycobacterium tuberculosis.  M. tuberculosis (Mtb) is a dreadful pathogen which survives within the hostile environment of macrophage; hence it is not surprising that it would employ a highly efficient DNA repair machinery to exist in such an environment.  Mycobacterial genome contains several putative HNH nucleases, Toxin-Antitoxin module and Methyltransferases under the SOS regulon. Our laboratory is focused to understand the role of SOS regulated nucleases in DNA repair. Investigation of these nucleases will provide a new direction to our understanding of Mycobacterial DNA repair and also the strategy it adopts to survive within the macrophages. Further, our research will help us to answer the following long standing questions ‘How the bacteria escape the onslaught of macrophages?’  and  How it adopts to survive within the hostile environment of the macrophages