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Source: https://theses.gla.ac.uk/71244/ Parent: https://theses.gla.ac.uk/view/subjects/QH345.html

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Regulation of RNA polymerase III transcription by the tumour suppressor p53

Crighton, Diane (2002) Regulation of RNA polymerase III transcription by the tumour suppressor p53. PhD thesis, University of Glasgow.

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Printed Thesis Information: https://eleanor.lib.gla.ac.uk/record=b2121908

Abstract

The tumour suppressor protein p53 is inactivated in a large proportion of human cancers. p53 controls growth and proliferation, through multiple mechanisms, including the ability to regulate transcription. p53 can function as a general repressor of RNA polymerase (pol) III transcription. Pol III is responsible for transcribing a variety of small stable RNAs including tRNA, 5S rRNA, and the adenoviral VA1 RNA. p53 targets TFIIIB, a TBP-containing factor that is essential for recruitment of pol III to its templates. This study investigates the TFIIIB-p53 interaction, and how it serves to regulate pol III-transcribed genes. p53 does not disrupt the interaction between the TFIIIB subunits, TBP and Brf1. It does, however, prevent association of TFIIIB with the pol III specific factor TFIIIC2, and pol III itself Immobilised template and chromatin immunoprecipitation analysis show that p53 prevents the recruitment of TFIIIB, but not TFIIIC2, to the tRNA promoter. Pol III repression cannot be attributed to one clearly defined region of p53. Sequence within both the N- and C-termini are essential, and the central core domain is also implicated in playing a role. Evidence is provided here that p53-mediated repression of tRNA genes occurs via a trichostatin A-sensitive histone deacetylase independent mechanism. p53 is deregulated or mutated in the vast majority of human cancers. Individuals who inherit mutant forms of p53 can suffer from Li-Fraumeni Syndrome (LFS), a familial cancer syndrome associated with a range of malignancies. Here is shown that pol III transcriptional activity is often highly elevated in primary fibroblasts from Li-Fraumeni patients, especially if the germline p53 mutation is followed by loss of the remaining allele. Deregulation of p53 function through the action of various oncoproteins can also contribute to carcinogenesis. E6 from human papilloma virus can bind to p53 and neutralise its function and E6 releases pol III from p53-mediated repression. Induction of the Mdm2 regulating protein p14ARF results in a p53-mediated repression of pol III activity. p53 does not interfere with normal cellular growth and development; it is, however, rapidly induced in response to cellular stress. Here it is shown that the DNA-damaging agent MMS provokes a p53 response that correlates with a dramatic pol III transcriptional repression. Collectively the data presented here support the idea that p53 can directly repress pol III transcription through interactions with the basal pol III machinery. p53 status can have a profound effect upon pol III activity; the precise circumstances under which such control becomes physiologically important however, remains to be determined.

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