Amino acid-dependent signaling <i>via</i> S6K1 and MYC is essential for regulation of rDNA transcription

// Jian Kang 1 , Eric P. Kusnadi 1 , Allison J. Ogden 1 , Rodney J. Hicks 2,3 , Lukas Bammert 4 , Ulrike Kutay 4 , Sandy Hung 5 , Elaine Sanij 1 , Ross D. Hannan 1,2,6,7,8,9 , Katherine M. Hannan 6,9 and Richard B. Pearson 1,2,6,7 1 Oncogenic Signaling and Growth Control Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria, Australia 2 Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia 3 Molecular Imaging and Targeted Therapeutics Laboratory, Cancer Therapeutics Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia 4 Institute of Biochemistry, Department of Biology, Swiss Federal Institute of Technology Zurich, Zurich, Switzerland 5 Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital & Department of Ophthalmology, University of Melbourne, East Melbourne, Victoria, Australia 6 Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia 7 Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia 8 School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia 9 Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberaa, ACT, Australia Correspondence to: Richard B. Pearson, email: // Katherine M. Hannan, email: // Keywords : amino acids, rDNA transcription, S6K1, MYC, Gerotarget Received : June 08, 2016 Accepted : June 15, 2016 Published : June 30, 2016 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.