Dysregulation of RNA polymerase I transcription during disease

Abstract

Transcription of the ribosomal RNA genes by the dedicated RNA polymerase I enzyme and subsequent processing of the ribosomal RNA are fundamental control steps in the synthesis of functional ribosomes. Dysregulation of Pol I transcription and ribosome biogenesis is linked to the etiology of a broad range of human diseases. Diseases caused by loss of function mutations in the molecular constituents of the ribosome, or factors intimately associated with RNA polymerase I transcription and processing are collectively termed ribosomopathies. Ribosomopathies are generally rare and treatment options are extremely limited tending to be more palliative than curative. Other more common diseases are associated with profound changes in cellular growth such as cardiac hypertrophy, atrophy or cancer. In contrast to ribosomopathies, altered RNA polymerase I transcriptional activity in these diseases largely results from dysregulated upstream oncogenic pathways or by direct modulation by oncogenes or tumor suppressors at the level of the RNA polymerase I transcription apparatus itself. Ribosomopathies associated with mutations in ribosomal proteins and ribosomal RNA processing or assembly factors have been covered by recent excellent reviews. In contrast, here we review our current knowledge of human diseases specifically associated with dysregulation of RNA polymerase I transcription and its associated regulatory apparatus, including some cases where this dysregulation is directly causative in disease. We will also provide insight into and discussion of possible therapeutic approaches to treat patients with dysregulated RNA polymerase I transcription. This article is part of a Special Issue entitled: Transcription by Odd Pols.

Figure 1. Regulation of RNA Polymerase I transcription by factors whose mutation is associated with genetic diseases

A schematic illustrating the sites of action where disease associated factors, including treacle, blooms syndrome helicase (BLM), werner helicase (WRN), cockayne syndrome B (CSB), plant homeodomain finger protein 8 (PHF8) and Filamin A, regulate RNA Polymerase I transcription. UBF: upstream binding factor; SL-1: selectivity factor 1; Pol I: RNA polymerase I; TTF-1: termination transcription factor 1; UCE: upstream control element;

Figure 2. Modulation of RNA Polymerase I transcription by oncogenes and tumour suppressors

A schematic illustrating the sites of action where oncogenes and tumour suppressors regulate RNA polymerase I transcription in a positive (blue) or negative (red) fashion. UBF: upstream binding factor; SL-1: selectivity factor 1; Pol I: RNA polymerase I; TTF-1: termination transcription factor 1; UCE: upstream control element. Note; in addition to directly interacting with the rDNA repeat and core transcription components, c-MYC also indirectly modulates RNA Polymerase I transcription by coordinating the increased expression of a cohort of Pol II transcribed genes termed the "Pol I regulon" which comprises over 90% of the core Pol I transcription factor complex including UBF, RRN3 and RNA Polymerase I subunits.

Figure 3. Modulation of RNA Polymerase I transcription by oncogenic and tumor suppressor signaling pathways

A schematic illustrating the sites of action where signaling molecules regulate RNA polymerase I in a positive (blue) or negative (red) fashion. UBF: upstream binding factor; SL-1: selectivity factor 1; Pol I: RNA polymerase I; TTF-1: termination transcription factor 1; UCE: upstream control element;