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Inhibition of RNA polymerase I transcription initiation by CX-5461 activates non-canonical ATM/ATR signaling.
Oncotarget. 2016 Aug 02; 7(31):49800-49818.O

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.

Authors+Show Affiliations

Research Division, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria, Australia. Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia. Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.Research Division, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria, Australia.Research Division, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria, Australia. Institute for Molecular Medicine Finland, Biomedicum 2, Helsinki, Finland.Research Division, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.Research Division, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria, Australia. Josep Carreras Institute for Leukaemia Research (IJC), Campus ICO-HGTP, Badalona, Barcelona, Spain.Research Division, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria, Australia.Research Division, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria, Australia.Research Division, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria, Australia.The John Curtin School of Medical Research, Australian National University, Acton, ACT, Australia.The John Curtin School of Medical Research, Australian National University, Acton, ACT, Australia. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia. School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia.Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia. The John Curtin School of Medical Research, Australian National University, Acton, ACT, Australia.Research Division, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria, Australia. Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia.Research Division, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria, Australia. Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.QIMR Berghofer Medical Research Institute, Brisbane City, Qld, Australia.Research Division, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.Pimera Inc, San Diego, CA, USA.Research Division, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia. Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia.Research Division, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria, Australia. Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.Research Division, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria, Australia. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.Research Division, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria, Australia. Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia. The John Curtin School of Medical Research, Australian National University, Acton, ACT, Australia. School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27391441

Citation

Quin, Jaclyn, et al. "Inhibition of RNA Polymerase I Transcription Initiation By CX-5461 Activates Non-canonical ATM/ATR Signaling." Oncotarget, vol. 7, no. 31, 2016, pp. 49800-49818.
Quin J, Chan KT, Devlin JR, et al. Inhibition of RNA polymerase I transcription initiation by CX-5461 activates non-canonical ATM/ATR signaling. Oncotarget. 2016;7(31):49800-49818.
Quin, J., Chan, K. T., Devlin, J. R., Cameron, D. P., Diesch, J., Cullinane, C., Ahern, J., Khot, A., Hein, N., George, A. J., Hannan, K. M., Poortinga, G., Sheppard, K. E., Khanna, K. K., Johnstone, R. W., Drygin, D., McArthur, G. A., Pearson, R. B., Sanij, E., & Hannan, R. D. (2016). Inhibition of RNA polymerase I transcription initiation by CX-5461 activates non-canonical ATM/ATR signaling. Oncotarget, 7(31), 49800-49818. https://doi.org/10.18632/oncotarget.10452
Quin J, et al. Inhibition of RNA Polymerase I Transcription Initiation By CX-5461 Activates Non-canonical ATM/ATR Signaling. Oncotarget. 2016 Aug 2;7(31):49800-49818. PubMed PMID: 27391441.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of RNA polymerase I transcription initiation by CX-5461 activates non-canonical ATM/ATR signaling. AU - Quin,Jaclyn, AU - Chan,Keefe T, AU - Devlin,Jennifer R, AU - Cameron,Donald P, AU - Diesch,Jeannine, AU - Cullinane,Carleen, AU - Ahern,Jessica, AU - Khot,Amit, AU - Hein,Nadine, AU - George,Amee J, AU - Hannan,Katherine M, AU - Poortinga,Gretchen, AU - Sheppard,Karen E, AU - Khanna,Kum Kum, AU - Johnstone,Ricky W, AU - Drygin,Denis, AU - McArthur,Grant A, AU - Pearson,Richard B, AU - Sanij,Elaine, AU - Hannan,Ross D, PY - 2016/03/17/received PY - 2016/06/13/accepted PY - 2016/7/9/pubmed PY - 2018/2/24/medline PY - 2016/7/9/entrez KW - CX-5461 KW - DNA damage signaling KW - RNA polymerase I KW - nucleolar stress response KW - rDNA SP - 49800 EP - 49818 JF - Oncotarget JO - Oncotarget VL - 7 IS - 31 N2 - 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. SN - 1949-2553 UR - https://www.unboundmedicine.com/medline/citation/27391441/Inhibition_of_RNA_polymerase_I_transcription_initiation_by_CX_5461_activates_non_canonical_ATM/ATR_signaling_ L2 - http://www.impactjournals.com/oncotarget/misc/linkedout.php?pii=10452 DB - PRIME DP - Unbound Medicine ER -