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RNA polymerases I and III, growth control and cancer

Nature Reviews Molecular Cell Biology volume 6, pages 69–78 (2005)Cite this article

Key Points

  • Cell growth depends on protein accumulation and is therefore tied to the synthesis of rRNA and tRNA by RNA polymerase (Pol) I and Pol III.

  • Restricting rRNA production will curtail cell growth and proliferation. Conversely, an activated Pol-I-specific transcription factor can be sufficient to accelerate proliferation.

  • Activation of the ERK signalling pathway increases transcription by Pol I and Pol III, allowing the coordinate synthesis of rRNA and tRNA to meet the growth requirements of the cell. This pathway is activated aberrantly in ∼30% of human cancers, due to defects in upstream factors, such as Ras.

  • Many cancers deregulate Myc, an oncoprotein that directly activates the synthesis of rRNA and tRNA. Both Myc and ERK also induce many other components of the protein synthetic apparatus, thereby increasing the capacity for translation and therefore growth.

  • Some tumour types consistently overexpress specific components of the Pol I or Pol III machinery, which indicates that there is selective pressure to increase the output of these transcription systems as cancers develop.

  • Production of rRNA and tRNA is restrained by three cardinal tumour suppressors, RB, p53 and ARF — this clearly illustrates the importance of controlling the levels of these products. Such restraint is compromised in most, if not all, cancers, which allows a dangerous increase in the capacity of a cell for biosynthesis and growth.

  • Repression of transcription by Pol I and Pol III could make an important contribution to the growth-control functions of these tumour suppressors.

Abstract

Transcription of rRNA and tRNA genes by RNA polymerases I and III is essential for sustained protein synthesis and is therefore a fundamental determinant of the capacity of a cell to grow. When cell growth is not required, this transcription is repressed by retinoblastoma protein, p53 and ARF. However, inactivation of these tumour suppressors in cancers deregulates RNA polymerases I and III, and oncoproteins such as Myc can stimulate these systems further. Such events might have a significant impact on the growth potential of tumours.

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Figure 1: Basal human Pol I and Pol III transcription complexes.
Figure 2: ERK targets that stimulate protein synthesis and therefore cell growth.
Figure 3: Cross-talk between p53, ARF and ribosome biosynthesis.
Figure 4: The RB pathway has several effects on transcription.
Figure 5: Induction of rRNA and tRNA synthesis by mitogens.

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Acknowledgements

Work in the author's laboratory is funded by Cancer Research UK, the Association for International Cancer Research, the Wellcome Trust, the Medical Research Council and the Biotechnology and Biosciences Research Council.

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Authors and Affiliations

  1. Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK

    Robert J. White

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DATABASES

OMIM

Burkitt lymphoma

Li–Fraumeni syndrome

Swiss-Prot

ARF

CBP

eIF4E

HDM2

L11

MAD1

Myc

nucleophosmin

p53

p107

p130

RB

SL1

TBP

TFIIIB

TIF1A

UBF

FURTHER INFORMATION

Robert White's laboratory

Glossary

rRNA

(ribosomal RNA). An RNA that carries out essential structural and catalytic roles within the ribosome. The Pol I products (the 28S, 18S and 5.8S rRNAs) are sometimes referred to as the large rRNAs to distinguish them from the Pol III product 5S rRNA.

tRNA

(transfer RNA). A short RNA that functions as an essential adaptor to translate the genetic information carried by mRNA into the sequence of amino acids in a polypeptide. This is possible because each tRNA only recognizes a particular amino acid and matches it to specific codons in the mRNA.

7SL RNA

An essential RNA component of the signal-recognition particle.

SIGNAL-RECOGNITION PARTICLE

A complex that is responsible for inserting nascent polypeptides into or through cell membranes; it identifies an N-terminal signal sequence that is carried by proteins destined for secretion or membrane localization.

SHORT INTERSPERSED NUCLEAR ELEMENT

(SINE). A pseudogene derived from tRNA or 7SL RNA that is propagated by retrotransposition. SINEs are typically 200–300 bp long and contain functional Pol III promoters. They are highly abundant in mammalian genomes, especially in humans, where the Alu SINE family constitutes ∼10% of the genomic DNA.

INITIATOR tRNA

The tRNA that is responsible for bringing the first amino acid to the start of the message.

TATA-BINDING PROTEIN

(TBP). A small, highly conserved protein that binds the TATA motif in gene promoters, but is also used by genes that lack TATA boxes. TBP is essential for the expression of rRNA and all Pol-III-transcribed genes, as well as many Pol II templates.

CHROMATIN IMMUNOPRECIPITATION

A technique for determining whether a protein binds to a particular region of the genome in vivo. It involves treating live cells with formaldehyde to form nonspecific crosslinks between the DNA and any associated proteins. The cells are then lysed, the genomic DNA is sheared into small fragments and the protein of interest is immunoprecipitated. Any protein-associated DNA is then removed and analysed by PCR.

POLYOMAVIRUS

A small DNA tumour virus that causes tumours in mice.

U6 SMALL NUCLEAR RNA

(U6 snRNA). snRNA molecules are small, untranslated RNA molecules that function in the nucleus by guiding the assembly of macromolecular complexes on the target RNA to allow site-specific modifications or processing reactions to occur. U6 snRNA is an essential small nuclear (sn)RNA that is required for pre-mRNA splicing.

GST PULL-DOWN ASSAY

A technique that allows the detection of proteins that bind in vitro to an immobilized recombinant protein fused to glutathione S-transferase (GST).

LARGE T ANTIGEN

The transforming oncoprotein of the DNA tumour virus simian virus 40 (SV40).

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White, R. RNA polymerases I and III, growth control and cancer. Nat Rev Mol Cell Biol 6, 69–78 (2005). https://doi.org/10.1038/nrm1551

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