TTF1 control of LncRNA synthesis delineates a tumor suppressor pathway directly regulating the ribosomal RNA genes

Author:

Sibai Dany S.123,Tremblay Michel G.1,Lessard Frédéric1,Tav Christophe123,Sabourin‐Félix Marianne1,Robinson Mark4,Moss Tom123ORCID

Affiliation:

1. St‐Patrick Research Group in Basic Oncology, Cancer Division of the Quebec University Hospital Research Centre Laval University Quebec City Quebec Canada

2. Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine Laval University Quebec City Quebec Canada

3. Cancer Research Centre Laval University Quebec City Quebec Canada

4. Department of Molecular Life Sciences University of Zurich Zurich Switzerland

Abstract

AbstractThe tumor suppressor p14/19ARF regulates ribosomal RNA (rRNA) synthesis by controlling the nucleolar localization of Transcription Termination Factor 1 (TTF1). However, the role played by TTF1 in regulating the rRNA genes and in potentially controlling growth has remained unclear. We now show that TTF1 expression regulates cell growth by determining the cellular complement of ribosomes. Unexpectedly, it achieves this by acting as a “roadblock” to synthesis of the noncoding LncRNA and pRNA that we show are generated from the “Spacer Promoter” duplications present upstream of the 47S pre‐rRNA promoter on the mouse and human ribosomal RNA genes. Unexpectedly, the endogenous generation of these noncoding RNAs does not induce CpG methylation or gene silencing. Rather, it acts in cis to suppress 47S preinitiation complex formation and hence de novo pre‐rRNA synthesis by a mechanism reminiscent of promoter interference or occlusion. Taken together, our data delineate a pathway from p19ARF to cell growth suppression via the regulation of ribosome biogenesis by noncoding RNAs and validate a key cellular growth law in mammalian cells.

Publisher

Wiley

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