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RNA polymerase III transcription can be derepressed by oncogenes or mutations that compromise p53 function in tumours and Li-Fraumeni syndrome

Oncogene volume 21, pages 2961–2970 (2002)Cite this article

Abstract

RNA polymerase (pol) III synthesizes essential small RNAs, including tRNA and 5S rRNA. Wild-type p53 can repress pol III transcription both in vitro and in vivo. Many tumours carry substitutions in p53 which have selective effects on its functions. We identify tumour-derived mutations that compromise the ability of p53 to regulate pol III transcription. Furthermore, substitution R175H, the most common mutation in cancers, converts p53 from a repressor to an activator of pol III. Oncoproteins neutralize p53 in some tumours; we show that human papillomavirus E6 and cellular hdm2 can both release pol III from repression by p53. These data suggest that the restraining influence of p53 on pol III will be lost in many tumours. In addition to these features of sporadic cancers, some individuals inherit mutant forms of p53 and consequently suffer from Li-Fraumeni syndrome, showing genetic predisposition to certain malignancies. We find 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. Our data suggest that p53 status can have a profound effect upon pol III transcription and hence on the biosynthetic capacity of cells.

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Acknowledgements

We wish to thank Arnold Berk, Saveria Campo, Lucio Comai, John Goddard, Sheila Graham, Nick La Thangue and Karen Vousden for plasmids. This work was funded by project grant SP2314/0102 to RJ White from Cancer Research UK. RJ White is a Jenner Research Fellow of the Lister Institute of Preventive Medicine.

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Authors and Affiliations

  1. Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, Davidson Building, University of Glasgow, Glasgow, G12 8QQ, UK

    Torsten Stein, Diane Crighton & Robert J White

  2. Cancer Research UK Department of Cancer Genetics, Paterson Institute for Cancer Research, Wilmslow Road, Manchester, M20 9BX, UK

    John M Boyle & Jennifer M Varley

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  1. Torsten Stein
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Correspondence to Robert J White.

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Stein, T., Crighton, D., Boyle, J. et al. RNA polymerase III transcription can be derepressed by oncogenes or mutations that compromise p53 function in tumours and Li-Fraumeni syndrome. Oncogene 21, 2961–2970 (2002). https://doi.org/10.1038/sj.onc.1205372

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