Regulation of Eukaryotic Transcription (RET)
Cell employs RNA polymerase enzymes to read genomic information in response to its ever-changing needs. Our research focuses on RNA polymerase I (Pol I) that produces ribosomal RNA – the building block of cellular protein factories. Excessively active Pol I allows cancer cells to grow beyond normal controls. To understand how the function of Pol I is regulated in normal and sick cells, we investigate the molecular events that take place when Pol I begins the production of ribosomal RNA.
The first step of gene expression is carried out by RNA polymerases that synthesize RNA-copies of genes in the process known as transcription. The RNA products serve as blueprints of protein synthesis, gene expression regulators or structural-and-functional constituents of large molecular machines, such as ribosomes. Perhaps the most fundamental information processing and decision making steps in the cell determine which genes and how much the RNA polymerase transcribes. Understanding how transcription and its regulation happen at the level of detailed molecular mechanisms is the scientific mission of our laboratory. Our work specifically focuses on transcription in eukaryotic organisms.
Our current main research project is to understand how RNA polymerase I (Pol I) initiates transcription. Pol I is specialized to produce ribosomal RNA precursor, from which the cell processes the main functional RNA parts of ribosomes. The central importance of Pol I bases on the fact that it is responsible for more than 60% of all RNA synthesis in growing cells. We wish to understand the identity, sequence and quantitative parameters of the molecular steps that Pol I takes when it starts to synthesize ribosomal RNA. Our research approach to understand the molecular mechanisms of Pol I function and regulation heavily depends on biochemical, enzyme kinetic and single-molecule fluorescence microscopy tools that allow to monitor the action of isolated Pol I protein apparatus in real-time.
The activity of RNA polymerase I apparatus is heavily regulated by the signaling pathways that control cell growth and maintenance. This regulatory balance is lost in many types of cancer leading to abnormally high Pol I activity and, hence, protein synthesis capacity in the sick cells. At the same time, the dependence of rapidly growing cancer cells on exceedingly efficient Pol I apparatus implies that Pol I specific inhibitors might be employed to treat cancer. The first cancer drug (CX-5461) harnessing this therapeutic strategy has indeed recently entered clinical trials. Our work expands understanding of the basic molecular mechanism of Pol I. The identified mechanisms may be utilized in the development of new Pol I inhibitors and cancer drugs.