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Regulation of RNA polymerase III transcription during transformation of human IMR90 fibroblasts with defined genetic elements

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posted on 24.11.2017 by Stéphanie Durrieu-Gaillard, Hélène Dumay-Odelot, Galina Boldina, Nicolas J. Tourasse, Delphine Allard, Fabrice André, Françoise Macari, Armelle Choquet, Pauline Lagarde, Guillaume Drutel, Thierry Leste-Lasserre, Marion Petitet, Tom Lesluyes, Lydia Lartigue-Faustin, Jean-William Dupuy, Frédéric Chibon, Robert G. Roeder, Dominique Joubert, Stéphan Vagner, Martin Teichmann

RNA polymerase (Pol) III transcribes small untranslated RNAs that are essential for cellular homeostasis and growth. Its activity is regulated by inactivation of tumor suppressor proteins and overexpression of the oncogene c-MYC, but the concerted action of these tumor-promoting factors on Pol III transcription has not yet been assessed. In order to comprehensively analyse the regulation of Pol III transcription during tumorigenesis we employ a model system that relies on the expression of five genetic elements to achieve cellular transformation. Expression of these elements in six distinct transformation intermediate cell lines leads to the inactivation of TP53, RB1, and protein phosphatase 2A, as well as the activation of RAS and the protection of telomeres by TERT, thereby conducting to full tumoral transformation of IMR90 fibroblasts. Transformation is accompanied by moderately enhanced levels of a subset of Pol III-transcribed RNAs (7SK; MRP; H1). In addition, mRNA and/or protein levels of several Pol III subunits and transcription factors are upregulated, including increased protein levels of TFIIIB and TFIIIC subunits, of SNAPC1 and of Pol III subunits. Strikingly, the expression of POLR3G and of SNAPC1 is strongly enhanced during transformation in this cellular transformation model. Collectively, our data indicate that increased expression of several components of the Pol III transcription system accompanied by a 2-fold increase in steady state levels of a subset of Pol III RNAs is sufficient for sustaining tumor formation.


This work was supported by the Ligue Contre le Cancer; INCa; National Institute of Health and Medical Research (INSERM); CNRS; National Institute of Health (NIH).