Regulation of RNA polymerase III transcription by Maf1 in mammals . (360G-Wellcome-081977_Z_07_Z)

The rate of transcription by RNA polymerase (pol) III is a major determinant of a cell s capacity to grow. As such, it is subject to stringent controls that ensure output is appropriate for prevailing conditions. Abnormally elevated pol III transcription is a feature of hyperproliferative and cardiovascular diseases. Genetic and biochemical studies have shown that in Saccharomyces cerevisiae a repressor called Maf1 binds and inhibits pol III in response to a wide range of stresses, such as DN A damage or nutrient deprivation. Indeed, evidence has been presented that Maf1 mediates pol III regulation under all circumstances examined in this yeast. We have found a homologue of Maf1 that potently represses pol III transcription in mouse and human cells. However, the situation is much more complex in mammals, which express a variety of factors that control pol III transcription directly and are not found in yeast, including RB, p53 and c-Myc. This project aims to characterise the phys iological role of Maf1 in mammals, by identifying conditions where it mediates a pol III regulatory response. It also aims to determine the mechanism(s) used by Maf1 to inhibit transcription.