Dr Alessandro Vannini, Vannini Group
RNA polymerase III-transcribed genes are a source of short metabolic RNAs, such as tRNAs and 5S rRNA, which are essential for cell growth and have oncogenic potential. The RNA polymerase III transcription apparatus involves several transcription factors to achieve faithful transcription. However, the transcription factor TFIIIB is ultimately required to recruit RNA polymerase III at its target genes and to form a stable pre-initiation complex capable of melting the DNA and, subsequently, initiate transcription.
Our research interests focus mainly in three areas:
In humans, several tumour suppressors proteins and oncogenes interact directly with the transcription factor TFIIIB and, as a consequence, modulate RNA polymerase III occupancy at target genes. During carcinogenesis, this layer of regulation is lost, resulting in an augmented RNA polymerase III transcriptional output.
Our research is aimed at mechanistically understanding the role of RNA polymerase III deregulation in cancer. We are currently studying the architecture and function of the RNA polymerase III pre-initiation complex and the association of specific tumour suppressors proteins and oncogenes with components of the RNA polymerase III machinery, using crystallography and EM.
Regulation of RNA polymerase III activity in response to extracellular and intracellular signals involve additional factors. These include the global negative regulator Maf1 and upstream kinases, such as CK2 and TORC1, which physically interact with the transcription apparatus and modulate its activity in a Maf1-dependent manner. These kinases complexes regulate multiple cellular processes, such as ribosome biogenesis, DNA damage repair, chromosome condensation and cohesion, and cell-cycle progression. Which is why we are interested in understanding how these regulatory complexes are specifically recruited and assembled at RNA polymerase III genes.