Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
ReviewDysregulation of RNA polymerase I transcription during disease☆
Highlights
► Dysregulation of RNA polymerase I transcription and ribosome biogenesis is linked to a broad range of human diseases. ► Ribosomopathies, hypertrophy, atrophy and cancer are all associated with dysregulation of RNA polymerase I transcription. ► Possible therapeutic approaches to treat patients with dysregulated RNA polymerase I transcription.
Introduction
Transcription of the ~ 200 copies of ribosomal RNA genes (rDNA), present in the mammalian haploid genome, by the dedicated RNA polymerase I (Pol I) enzyme and subsequent processing of the ribosomal RNA (rRNA) are fundamental control steps in the synthesis of functional ribosomes (reviewed in [1], [2], [3]). If rRNA synthesis is inhibited, cells undergo cell cycle arrest associated with apoptosis, senescence or autophagy depending on the cell type. Conversely, accelerated rRNA synthesis tightly correlates with cellular proliferation rates. Not surprisingly, it is becoming increasingly clear that dysregulation of Pol I transcription and ribosome biogenesis is linked to the etiology of a broad range of human diseases.
Perhaps the best recognized diseases associated with dysregulated ribosome biogenesis are caused by loss of function mutations in the molecular constituents of the ribosome or factors intimately associated with Pol I transcription and processing collectively termed ribosomopathies (Table 1) [4]. This class of genetic diseases includes those caused by mutations in ribosomal proteins for example Diamond–Blackfan anemia and 5q- syndrome [4], [5], [6], [7]. Alternatively they are associated with mutations in modulators or components which impact on Pol I transcription, such as is the case for Treacher Collins Syndrome [8], [9], [10], or Blooms and Werner Syndromes [11], [12], [13]. Other ribosomopathies are associated with mutations that affect rRNA processing and modification such as Shwachman–Diamond Syndrome [14], Dyskeratosis Congenita [15], Cartilage Hair Hypoplasia [16], [17], North American Indian childhood cirrhosis [18], [19], Bowen–Conradi Syndrome [20] and alopecia, neurological defect and endocrinopathy (ANE) Syndrome [21] (Table 1). Ribosomopathies are generally rare and treatment options are unfortunately extremely limited tending to be more palliative than curative.
In addition to ribosomopathies, dysregulation of Pol I activity is common in diseases associated with profound changes in cellular growth such as cardiac hypertrophy, atrophy or cancer. Indeed abnormal nucleoli, the site of Pol I transcription, has been used as a marker of aggressive tumors for over 100 years, well before the function of the nucleolus was known. In contrast to ribosomopathies, altered Pol I transcriptional activity in these diseases largely results from dysregulated upstream signaling pathways and consequently altered expression or activity of factors directly involved in Pol I transcription. In the case of cancer, this includes hyperactivation of classic oncogenes and upstream oncogenic signaling pathways (e.g., epidermal growth factor (EGF) receptor, c-MYC and mammalian target of rapamycin (mTOR)/PI3K/AKT), or release from repression by tumor suppressors (e.g., p53, retinoblastoma protein (pRb)). While it has been debated for some time whether the dysregulation of Pol I is a cause or a consequence in diseases such as cancer, recent studies have gone a long way to answer this question [22], [23]. Using genetic approaches and small molecule inhibitors of Pol I activity Bywater et al. [22] provided definitive proof that hyperactive Pol I transcription is required for the malignant phenotype of certain cancers and targeting Pol I can be used as a therapeutic approach to treat malignancy with few side effects on normal cells [22].
These examples illustrate how far the concept of dysregulated Pol I transcription and its contribution to human disease has come in the past 10 years. However, in reality we are just at the beginning of the long journey to fully understanding the etiology and development of the diverse array of pathologies and proliferative disorders associated with ribosomopathies and deranged Pol I transcription. While a number of recent publications have covered ribosomopathies associated with mutation in ribosomal proteins and processing/assembly factors (see reviews [4], [24], [25]), here we review our current knowledge of human diseases specifically associated with dysregulation of Pol I transcription and its associated regulatory apparatus, including some cases where this dysregulation is directly causative. Throughout the review, for clarity, we will utilize the mammalian/human terminology for the Pol I transcription factors. We will also provide insight into and discussion of possible therapeutic approaches to treat patients with dysregulated Pol I transcription.
Section snippets
Diseases with mutations in factors directly associated with RNA polymerase I transcription
A number of factors have been identified that co-immunoprecipitate with the Pol I transcription components and whose encoding genes when mutated result in both dysregulated Pol I transcription and a specific human disease syndromes (Table 1; Fig. 1). These include the proteins treacle, blooms syndrome helicase, werner helicase, cockayne syndrome B, plant homeodomain finger protein 8 and Filamin A which underlie the diseases Treacher Collins Syndrome, Blooms and Werner Syndromes, Cockayne
Diseases associated with modulation of Pol I transcriptional activity through dysregulation of upstream signaling pathways
Proliferative growth requires that protein synthesis, and thus ribosome availability, can match cell cycle rates. Insufficient protein synthesis and the daughter cells will progressively get smaller, whereas a surplus results in enlarged cells and is often associated with cellular transformation. Consequently, in normal cells Pol I transcription and ribosome biogenesis is tightly coordinated with the cell cycle in order to respond to changes in demand for proliferative growth. Interestingly,
Targeting Pol I transcription as a therapy for disease
The previous sections have summarized the plethora of data demonstrating that Pol I transcription of the rRNA genes is aberrantly regulated in a broad range of diseases associated with dysregulation of cellular growth, most notable muscle hypertrophy and cancer. This dysregulation is achieved either through direct mutations in components of the Pol I transcription apparatus, as found in ribosomopathies, or more commonly through direct or indirect effects of oncogenic and tumor suppressor
Summary and perspectives
Ribosome biogenesis is fundamental for cell growth, proliferation and survival. However, it is now becoming clear that deranged ribosome synthesis and function underlies a growing list of ribosomopathies that often result in catastrophic outcomes for patients. These syndromes are due to germline and/or somatic mutations, and include Treacher Collins and Shwachman–Diamond Syndromes. While deranged rDNA transcription almost certainly drives Treacher Collins Syndrome, the diverse phenotypes
Conflict of interest
R.D. Hannan is a member of the Scientific Advisory Board for Cylene.
Acknowledgments
Due to space limitations we have not been able to individually cite many of the original publications that have contributed substantially to the field. We sincerely apologize to the authors of these publications. This work was supported by the National Health and Medical Research Council (NHMRC) of Australia project grants; NHMRC Research Fellowship to R.D.H. and R.B.P.; Grants in Aid from the Prostate Cancer Foundation of Australia and the Leukemia Foundation of Australia; and NIH RO1 to L.I.R.
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2023, Biochimica et Biophysica Acta - Reviews on CancerCitation Excerpt :Ribosome biogenesis, a complex process responsible for the synthesis of ribosomal RNA subunits, is controlled by RNA polymerase 1 (Pol-1) machinery, and involved in cell growth and proliferation, and inhibited by melatonin. Its inhibition is associated with induction of cell death via apoptosis [102]. Indeed, melatonin was able to inhibit the expression of 45S pre-mRNA as well as molecules related to its synthesis, such as UBF and fibrillarin, by negatively regulating Pol-1 transcription.
The Nucleolus
2022, Encyclopedia of Cell Biology: Volume 1-6, Second EditionRNA polymerase I subunit 12 plays opposite roles in cell proliferation and migration
2021, Biochemical and Biophysical Research CommunicationsCitation Excerpt :Among which, the transcription of 45S pre-rRNA, a precursor for 28S, 18S, and 5.8S rRNA, is completed by RNA polymerase I [3]. Dysregulation of Pol I transcription causes genetic diseases, heart defects, and cancers [4,5]. For instance, mutations of POLRIC and POLRID are associated with the occurrence of Treacher Collins Syndrome [6].