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

Dany S Sibai1,2,3, Michel G Tremblay1, Frédéric Lessard1

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

Journal of Cellular Physiology
|May 20, 2024
PubMed

Insights

The tumor suppressor p19ARF regulates cell growth by controlling ribosome synthesis. It uses noncoding RNAs generated from ribosomal DNA to block pre-rRNA production, impacting cell proliferation.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • The tumor suppressor p14/19ARF influences ribosomal RNA (rRNA) synthesis by regulating Transcription Termination Factor 1 (TTF1) nucleolar localization.
  • The precise function of TTF1 in rRNA gene regulation and its impact on cell growth remain incompletely understood.

Purpose of the Study:

  • To elucidate the role of TTF1 in regulating rRNA genes and controlling cell growth.
  • To investigate the mechanism by which TTF1 influences ribosome biogenesis and cellular proliferation.

Main Methods:

  • Analysis of TTF1 expression and its effect on ribosome production.
  • Investigation of noncoding RNA (lncRNA and pRNA) generation from ribosomal DNA spacer promoters.
  • Assessment of promoter interference mechanisms in rRNA gene regulation.

Main Results:

  • TTF1 expression dictates the cellular ribosome content, thereby regulating cell growth.
  • Noncoding RNAs generated from "Spacer Promoter" duplications act as a roadblock to 47S pre-rRNA synthesis.
  • Endogenous noncoding RNA production does not induce CpG methylation or gene silencing but suppresses preinitiation complex formation.

Conclusions:

  • A novel pathway from p19ARF to cell growth suppression is delineated, mediated by noncoding RNA regulation of ribosome biogenesis.
  • The findings reveal a mechanism of promoter interference or occlusion in rRNA gene regulation by endogenous noncoding RNAs.
  • This study validates a critical cellular growth law in mammalian cells concerning ribosome production.
Keywords:
RNAgene regulationlong noncodingribosomalribosomestumor suppression

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