Abstract
RNA polymerase (pol) III transcription is a major determinant of biosynthetic capacity, providing essential products such as tRNA and 5S rRNA. It is controlled directly by the tumour suppressors RB and p53. High-risk types of human papillomavirus (HPV), such as HPV16, express the oncoproteins E6 and E7 that can inactivate p53 and RB, respectively. Accordingly, both E6 and E7 stimulate pol III transcription in cultured cells. HPV16-positive cervical biopsies express elevated levels of tRNA and 5S rRNA when compared to biopsies that test negative for HPV or are infected with the lower risk HPV11. Integration of viral DNA into the host cell genome stimulates expression of E6 and E7 and correlates with induction of tRNA and 5S rRNA. Expression of mRNA encoding the pol III-specific transcription factor Brf1 also correlates with the presence of integrated HPV16. Brf1 levels are limiting for tRNA and 5S rRNA synthesis in cervical cells. Furthermore, pol III-transcribed genes that do not use Brf1 are not induced in HPV16-positive biopsies. Three complementary mechanisms may therefore allow high-risk HPV to stimulate production of tRNA and 5S rRNA: E6-mediated removal of p53; E7-mediated neutralization of RB; and induction of Brf1. The resultant increase in biosynthetic capacity may contribute to deregulated cell growth.
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Acknowledgements
We would like to thank Margaret Stanley and Paul Lambert for W12 cells and Shona Murphy for the 7SK gene. We are also grateful to Tina Dalianis and Saveria Campo for helpful discussions. This work was funded by a Medical Research Council studentship to NLD, by a fellowship to DAA from the UICC, and by the following grants to RJW: 01-263 from the Association for International Cancer Research, BB5/8/0711X from the Biotechnology and Biological Sciences Research Council, and C1288/A2138 from Cancer Research UK.
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Daly, N., Arvanitis, D., Fairley, J. et al. Deregulation of RNA polymerase III transcription in cervical epithelium in response to high-risk human papillomavirus. Oncogene 24, 880–888 (2005). https://doi.org/10.1038/sj.onc.1208031
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DOI: https://doi.org/10.1038/sj.onc.1208031
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