Trends in Biochemical Sciences
RNA-polymerase-I-directed rDNA transcription, life and works
Introduction
A remarkable 50% of nascent RNA synthesis in a cell is accounted for by the transcription of ribosomal RNA (rRNA) genes 1, 2, 3, 4, 5, 6, 7, which direct and support the production of several millions of ribosomes [8]. Eukaryotic cells have evolved a ribosomal DNA (rDNA) transcription machinery that incorporates RNA polymerase I (pol I), an enzyme dedicated to this pursuit. rDNA transcription is confined to the nucleolus, which is the site of ribosome biogenesis. There are hundreds of copies of rRNA genes in mammalian and yeast cells; they are arranged in clusters as tandem head-to-tail repeats, and constitute the nucleolar organizing regions (NORs; Figure 1). The primary rRNA transcript synthesized by mammalian pol I is processed into the mature 18S, 5.8S and 28S rRNAs which, together with the 5S rRNA transcribed by RNA polymerase III (pol III), constitute the major catalytic and architectural components of the ribosome [9]. Crucially, there is a fine balance between the growth status of the cell and the accumulation of rRNAs, which is largely controlled at the level of rDNA transcription. Signalling pathways that affect cell growth in response to nutrients and growth factors and during the cell cycle have a direct influence on rRNA synthesis, with the downstream effectors of such pathways converging at the pol I transcription cycle. Here, we review recent progress in this area of research, primarily focusing on mammalian cells, and also touching on the potential impact of altered rRNA synthesis on the fate of the cell.
Section snippets
Pre-initiation complex formation
Transcription commences with the recruitment and assembly of pol I and other transcription factors into a pre-initiation complex (PIC) at the rRNA gene promoter. The mammalian rRNA gene promoter contains a core element, which is essential for accurate transcription initiation, and an upstream control element (UCE), which has a modulatory role; the spacing between these sequences is crucial, as is their relative orientation (Figure 1). In addition to these elements, there are distal
Control of rDNA transcription
The rate of cell growth and proliferation is directly proportional to the rate of protein synthesis, which is intricately linked to ribosome biogenesis and controlled at the level of rDNA transcription by pol I 1, 6, 52. Intracellular signals must coordinate the synthesis of rRNA with that of other ribosome building blocks and components of the protein translation machinery. Control of pol I transcription could involve either adjustments to the number of genes actively engaged in transcription
rRNA synthesis, cell growth, cell-cycle progression and cell fate
Certainly, there is a crucial role for rRNA synthesis in normal cell growth and in the adjustment of cell growth in response to growth factors and nutrient availability. Furthermore, rRNA levels influence cellular differentiation, cell fate and the development of an organism [72].
Cell growth (increase in size and mass) and cell proliferation (increase in cell number) are intricately linked in most cells. Cell growth is essential for cell-cycle progression and sustained cell proliferation, and
Concluding remarks and future perspectives
Significant advances have been made towards an understanding of the pol I transcription machinery (works) in the transcription cycle. Recent studies have shown that regulation of rDNA transcription is manifested via multiple pathways and mechanisms operating in parallel with distinct kinetics. The exact combination is likely to be dependent upon cell type and physiological status. Future research could indicate whether rDNA transcription and rRNA levels couple the capacity of a cell for growth
Acknowledgements
We thank Ann Beyer for providing the Miller spread image in Figure 1. We also thank Julian Blow, Taciana Kasciukovic, Angus Lamond, Kostya Panov, Shalini Patak, Neil Perkins and reviewers for insightful comments, and Ingrid Grummt for allowing us to quote unpublished data. Work in our laboratory is supported by the Wellcome Trust Senior Research Fellowship of J.C.B.M.Z. We apologize to colleagues whose work could not be included in this review owing to space constraints.
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