Abstract
Dysregulation of RNA polymerase I (Pol I)-dependent ribosomal DNA (rDNA) transcription is a consistent feature of malignant transformation that can be targeted to treat cancer. Understanding how rDNA transcription is coupled to the availability of growth factors and nutrients will provide insight into how ribosome biogenesis is maintained in a tumour environment characterised by limiting nutrients. We demonstrate that modulation of rDNA transcription initiation, elongation and rRNA processing is an immediate, co-regulated response to altered amino acid abundance, dependent on both mTORC1 activation of S6K1 and MYC activity. Growth factors regulate rDNA transcription initiation while amino acids modulate growth factor-dependent rDNA transcription by primarily regulating S6K1-dependent rDNA transcription elongation and processing. Thus, we show for the first time amino acids regulate rRNA synthesis by a distinct, post-initiation mechanism, providing a novel model for integrated control of ribosome biogenesis that has implications for understanding how this process is dysregulated in cancer.
Highlights
Mammalian cells rapidly and exquisitely regulate energy-consuming anabolic and energy-producing catabolic processes in response to altered levels of nutrients, growth factors, energy and oxygen in the environment
Similar effects of amino acidinduced 47/45S rRNA synthesis were observed in a second human cell line, the immortalized human BJ foreskin fibroblasts expressing h-TERT (BJ-T) (Figure S1A)
We examined the response of 47/45S pre-rRNA synthesis to growth factors in the absence of amino acids to assess the requirement of amino acids for growth factor-induced polymerase I (Pol I) transcription
Summary
Mammalian cells rapidly and exquisitely regulate energy-consuming anabolic and energy-producing catabolic processes in response to altered levels of nutrients, growth factors, energy and oxygen in the environment. An initiation-competent complex requires recruitment of RRN3 ( called TIF1A) whose activity is regulated by phosphorylation in response to various growth factors or stress stimuli [5, 6]. Pol I transcription generates the 47S pre-rRNA, which is rapidly processed to the 18S, 5.8S and 28S rRNAs in the nucleolus These mature rRNAs, together with the 5S rRNA transcribed by Pol III, form the RNA backbone of the ribosome. Given the critical link between cellular metabolism, ribosome biogenesis and cell growth, it is important to consider that as the solid tumor microenvironment is often poorly perfused due to inefficient neovascularisation, nutrient availability may be restricted [20]. Understanding how high rates of rDNA transcription and ribosome biogenesis are maintained in such a compromised environment will be important for identifying potential therapeutic targets for these cancers
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