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

Jaclyn E Quin, Keefe T Chan, Jennifer R Devlin, Donald P. Cameron, Jeannine Diesch, Carleen M Cullinane, Jessica Ahern, Amit S Khot, Nadine Hein, Amee J. George, Katherine M Hannan, Gretchen Poortinga, Karen E Sheppard, Kum Kum Khanna, Ricky W Johnstone, Denis J Drygin, Grant A McArthur, Richard B. Pearson, Elaine Sanij, Ross D. Hannan

Research output: Contribution to journalArticleResearchpeer-review

54 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)49800-49818
Number of pages19
JournalOncotarget
Volume7
Issue number31
DOIs
Publication statusPublished - 2016

Keywords

  • CX-5461
  • DNA damage signaling
  • Nucleolar stress response
  • RDNA
  • RNA polymerase I

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