Texas A&M University, College Station
National Center for Biological Sciences, Bangalore, India
After an undergraduate in Genetics and Chemistry and a Masters in Biotechnology from the University of Pune, I was recruited into Unilever’s research division in Bangalore. This was my first experience with independent lab work and I realized how incredibly exciting it is to be able to ask any question and design experiments to try to answer it. Recognizing the need for graduate studies, I joined the lab of Dr. James C. Sacchettini, a structural biologist at Texas A&M University. In his lab, I developed a fascination for biological problems that can be addressed using X-ray crystallography, focusing initially on nucleic acid recognition by diverse protein families. I worked on proteins that act as RNA quality-control factors, selectively associating with misfolded rRNAs, UV damaged RNAs and other small RNAs, targeting them towards degradation. This got me interested in the broader roles of RNA-mediated gene regulation in bacteria. It was at about this time that metabolite-sensing RNAs called riboswitches were being discovered. Riboswitches act as cellular signal sensors where a structural change is key for eliciting a genetic response. How RNAs might create the chemical complexity required to bind specific metabolites and thus function as signal sensors much like proteins, seemed to be a question ideally addressed by structural studies.
I therefore joined the lab of Dr. Wade C. Winkler (U.T. Southwestern Medical Center), a pioneer in the field of metabolite-sensing riboswitch RNAs, to address these questions. The Winkler lab was looking to welcome a structural biologist in the group, so I got a rather unique opportunity to independently establish a crystallography set-up in the lab. My research addressed two main areas of RNA-regulation. First, metallo-regulation was traditionally attributed only to protein-based regulators. This was especially true for transition metals, which require specialized coordination chemistry/geometry more easily presented in proteins. Whether and how RNAs might function as transition-metal sensors, was an open question. In collaboration with Dr. Ronald Breaker’s lab (Yale Univ.), we discovered a class of transition metal riboswitches. These studies opened up several new areas of research addressing the dynamics, biology and implications of RNA-based metallo-regulation in bacteria. Regulatory RNAs often function not in isolation, but as intricately woven protein-RNA networks. This cross-talk between regulatory RNAs and proteins is fundamentally important to bacterial biology, yet poorly understood. We also identified new RNA-protein binding proteins (the ANTAR proteins) that regulate gene expression.
In my lab at NCBS, we are interested in identifying protein-RNA networks that integrate responses to diverse stimuli by controlling bacterial gene expression. We are especially interested in understanding how these protein-RNA networks control genes involved in bacterial pathogenesis. To address this, we combine structural and biophysical approaches (particularly X-ray crystallography), with biochemical studies and gene expression studies in bacteria. We hope in the coming years to identify new modes of control in this largely uncharted terrain of protein-RNA mediated gene regulation.