Inhibition of RNA polymerase I transcription initiation by CX-5461 activates non-canonical ATM/ATR signaling

  • Oncotarget. 2016 Aug 2;7(31):49800-49818. doi: 10.18632/oncotarget.10452.
Jaclyn Quin  1  2  3 ,  Keefe T Chan  1 ,  Jennifer R Devlin  1  4 ,  Donald P Cameron  1  5 ,  Jeannine Diesch  1  6 ,  Carleen Cullinane  1 ,  Jessica Ahern  1 ,  Amit Khot  1 ,  Nadine Hein  7 ,  Amee J George  7  8  9 ,  Katherine M Hannan  2  7 ,  Gretchen Poortinga  1  10 ,  Karen E Sheppard  1  2  5 ,  Kum Kum Khanna  11 ,  Ricky W Johnstone  1  5  8 ,  Denis Drygin  12 ,  Grant A McArthur  1  5  8  10 ,  Richard B Pearson  1  2  5  13 ,  Elaine Sanij  1  8 ,  Ross D Hannan  1  2  5  7  9  13
Affiliations
  • 1. Research Division, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria, Australia.
  • 2. Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia.
  • 3. Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
  • 4. Institute for Molecular Medicine Finland, Biomedicum 2, Helsinki, Finland.
  • 5. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
  • 6. Josep Carreras Institute for Leukaemia Research (IJC), Campus ICO-HGTP, Badalona, Barcelona, Spain.
  • 7. The John Curtin School of Medical Research, Australian National University, Acton, ACT, Australia.
  • 8. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
  • 9. School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia.
  • 10. Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia.
  • 11. QIMR Berghofer Medical Research Institute, Brisbane City, Qld, Australia.
  • 12. Pimera Inc, San Diego, CA, USA.
  • 13. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
PMID: 27391441 DOI: 10.18632/oncotarget.10452
Abstract

RNA polymerase I (Pol I)-mediated transcription of the ribosomal RNA genes (rDNA) is confined to the nucleolus and is a rate-limiting step for cell growth and proliferation. Inhibition of Pol I by CX-5461 can selectively induce p53-mediated Apoptosis of tumour cells in vivo. Currently, CX-5461 is in clinical trial for patients with advanced haematological malignancies (Peter Mac, Melbourne). Here we demonstrate that CX-5461 also induces p53-independent cell cycle checkpoints mediated by ATM/ATR signaling in the absence of DNA damage. Further, our data demonstrate that the combination of drugs targeting ATM/ATR signaling and CX-5461 leads to enhanced therapeutic benefit in treating p53-null tumours in vivo, which are normally refractory to each drug alone. Mechanistically, we show that CX-5461 induces an unusual chromatin structure in which transcriptionally competent relaxed rDNA repeats are devoid of transcribing Pol I leading to activation of ATM signaling within the nucleoli. Thus, we propose that acute inhibition of Pol transcription initiation by CX-5461 induces a novel nucleolar stress response that can be targeted to improve therapeutic efficacy.

Keywords
CX-5461; DNA damage signaling; RNA polymerase I; nucleolar stress response; rDNA.
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