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Cell Cycle. 2018;17(5):605-615. doi: 10.1080/15384101.2017.1405881. Epub 2018 Jan 22.

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

Author information

1
a Université de Bordeaux , ARNA Laboratory , F-33076 Bordeaux , France.
2
b INSERM, U1212 - CNRS UMR 5320 , ARNA Laboratory , F-33000 Bordeaux , France.
3
c Institut Gustave Roussy , INSERM U981 , F-94805 Villejuif , France.
4
d Institut de Génomique Fonctionnelle , UMR 5203 CNRS , F-34000 Montpellier , France.
5
e Department of Biopathology , Institut Bergonié , Molecular Pathology Unit , F-33000 Bordeaux , France.
6
f Génétique et Biologie des Sarcomes- INSERM U916 , F- 33000 Bordeaux , France.
7
g Université de Bordeaux , F-33076 Bordeaux , France.
8
h NeuroCentre François Magendie , INSERM U862 , F-33077 Bordeaux , France.
9
i Université de Bordeaux , Plateforme Protéome - Centre Génomique Fonctionnelle Bordeaux , 33076 Bordeaux , France.
10
j The Rockefeller University , 1230 York Avenue, New York , NY 10065 , USA.
11
k Institut Curie , CNRS UMR 3348, F-91405 Orsay , France.

Abstract

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.

KEYWORDS:

7SK RNA; POLR3G; PP2A; RAS; RB1; RNA polymerase III; TERT; TP53; defined transformation; transcription

PMID:
29171785
PMCID:
PMC5969553
[Available on 2019-01-22]
DOI:
10.1080/15384101.2017.1405881

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