Inhibition of RNA polymerase I transcription initiation by CX-5461 activates non-canonical ATM/ATR signaling
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Jaclyn Quin1,2,11, Keefe T. Chan1, Jennifer R. Devlin1,12, Donald P. Cameron1,3, Jeannine Diesch1,13, Carleen Cullinane1, Jessica Ahern1, Amit Khot1, Nadine Hein4, Amee J. George4,5,6, Katherine M Hannan2,4, Gretchen Poortinga1,7, Karen E. Sheppard1,2,3, Kum Kum Khanna8, Ricky W. Johnstone1,3,5, Denis Drygin9, Grant A. McArthur1,3,5,7, Richard B. Pearson1,2,3,10, Elaine Sanij1,5,*, Ross D. Hannan1,2,3,4,6,10,*
1Research Division, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria, Australia
2Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia
3Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
4The John Curtin School of Medical Research, Australian National University, Acton, ACT, Australia
5Department of Pathology, University of Melbourne, Parkville, Victoria, Australia
6School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia
7Department of Medicine, St Vincent’s Hospital, University of Melbourne, Fitzroy, Victoria, Australia
8QIMR Berghofer Medical Research Institute, Brisbane City, Qld, Australia
9Pimera Inc, San Diego, CA, USA
10Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
11Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
12Institute for Molecular Medicine Finland, Biomedicum 2, Helsinki, Finland
13Josep Carreras Institute for Leukaemia Research (IJC), Campus ICO-HGTP, Badalona, Barcelona, Spain
*These authors contributed equally to this work
Elaine Sanij, email: [email protected]
Ross D. Hannan, email: [email protected]
Keywords: RNA polymerase I, rDNA, CX-5461, nucleolar stress response, DNA damage signaling
Received: March 17, 2016 Accepted: June 13, 2016 Published: July 06, 2016
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.
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