The emerging role of RNA polymerase I transcription machinery in human malignancy: a clinical perspective

Abstract

Ribosome biogenesis - the complex and highly coordinated cellular process leading to the production of ribosomes - is strictly dependent on the activity of RNA polymerase I (Pol I) transcriptional machinery. Pol I activity is continually increased in proliferating cells to sustain the increased demand for ribosome production and protein synthesis, which are necessary for appropriate cell growth and division. The integrity of the process of ribosome biogenesis represents an important sensor of cellular stress: when this process is altered, a tumor suppressor response is triggered, which leads to proliferative arrest. The present review focuses on the possible implications of Pol I targeting in the treatment of human malignancies.

Keywords: Pol I; RNA polymerase I inhibitors; cancer; cell cycle control; ribosome biogenesis.

Figure 1

Schematic representation of the organization of the ribosomal gene unit. The scheme illustrates the organization of the ribosomal gene unit, which is found tandemly repeated approximately 400 times in the human genome. One unit includes the promoter, the transcribed region, and the terminator. The major basal factors binding to the promoter region and required for ribosomal gene transcription are also shown. Abbreviations: ETS, external transcribed region; ITS, internal transcribed region; rDNA, ribosomal DNA; SL1, selectivity factor 1; TIF-1A, transcription initiation factor 1A; TTF-I, transcription terminator factor I; UBF, upstream binding factor; Pol I, RNA polymerase l.

Figure 2

Different effects of RNA polymerase I (Pol I) inhibition according to the function of the p53/pRb pathway. (A) Pol I inhibition induces G1/S cell cycle arrest through activation of the p53/pRb pathway. (B) In cells lacking the functional p53/pRb pathway, the inhibition of Pol I does not induce cell cycle arrest; rather, without a sufficient ribosomal complement, the cell divides and dies. Abbreviation: pRb, retinoblastoma protein.

Figure 3

Different effects of RNA polymerase I (Pol I) inhibition according to the rate of ribosome biogenesis. A hypothesis explaining the different sensitivity to ribosomal RNA (rRNA) transcription inhibition in cells with different rate of ribosomal biogenesis. rRNA synthesis requires the stoichiometric production of ribosomal proteins. (A) In cells with a low ribosomal biogenesis rate, inhibition of rRNA transcription produces a limited amount of ribosomal proteins (RPs) free to bind and inactivate murine double minute 2 (MDM2) protein. Some MDM2 molecules can still bind p53 for degradation. (B) In cells with a high ribosomal biogenesis rate, inhibition of rRNA transcription produces a large amount of RPs free to bind and inactivate the majority of MDM2 molecules, thus leading to p53 accumulation. Abbreviation: rDNA, ribosomal DNA.