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RNA polymerase III regulation by tumour suppressors and oncogenes

Because of the central role of RNA polymerase (Pol) III transcripts in basal cellular processes, the level of RNA Pol III transcription is a critical determinant of cell growth. In humans, RNA Pol III is tightly regulated in normal cells but this regulation is lost during tumorigenesis. Tumour suppressors, such as p53 and Rb, and oncogenes, such as c-Myc, have been shown to interact directly with the transcription factor III B (TFIIIB), modulating its interaction with RNA Pol III. During carcinogenesis, the release from repression by tumour suppressors and/or the activation of oncogenes give rise to an increased occupancy of RNA Pol III pre-initiation complexes at its target genes and, as a consequence, to an augmented Pol III transcriptional output.

RNA-polymerase-III-recruitment image
Our aim is to understand the underlying molecular mechanisms of RNA Pol III deregulation in cancer cells and we are planning to investigate biochemically and structurally the association of transcription factor TFIIIB with tumour suppressors and oncogenes. To date, no detailed structural data is available and the molecular basis of these interactions is poorly understood. Structural insights of these interactions will represent a framework to understand mechanistically the role of RNA Pol III deregulation in cancer cells and assess its potential as a therapeutic agent.