2. Academic Validation
  3. Inhibition of RNA polymerase I transcription initiation by CX-5461 activates non-canonical ATM/ATR signaling

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

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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