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Research overview

Professor Alessandro Vannini, Vannini Group

Eukaryotic transcription relies on three different RNA polymerases: RNA polymerase I (Pol) transcribes ribosomal RNA, RNA Polymerase II synthesizes messenger RNAs and RNA polymerase III produces short and non-translated RNAs, including the entire pool of tRNAs, which are essential for cell growth.

For a long time, it was assumed that only Pol II was regulated whereas Pol I and Pol III, being devoted to house-keeping genes, did not require such control. However, growing evidence show that RNA Polymerase III transcription is tightly regulated. Deregulation of its recruitment has been linked to neurodegenerative diseases and cancer.

RNA Pol III is recruited at only 3 types of promoters. While the type 1 and 2 are conserved from yeast to human, the type 3 promoters are found solely in higher eukaryotes. At the type 1 and 2, TFIIIC binds the promoter sequence to recruit TFIIIB that places the polymerase at the transcriptional start site. 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.

It is becoming increasingly clear that Pol III (and its associated factors) play a paramount role into genome structure and organisation. These extratranscriptional roles are effected through interactions with transposon machineries, SMC complexes and specific chromatin remodellers; we are aiming to obtain a detailed mechanistic understanding of these fundamental processes.

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