Journal article

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

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



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 t..

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Awarded by National Health and Medical Research Council (NHMRC) of Australia

Awarded by NHMRC

Funding Acknowledgements

This work was supported by the National Health and Medical Research Council (NHMRC) of Australia project grants (#1043884, 251608, 566702, 166908, 251688, 509087, 400116, 400120, 566876) and a NHMRC Program Grant (#1053792). Researchers were funded by NHMRC Fellowships (R.W.J, G.A.M. R.D.H, R.B.P), Cancer Council of Victoria Sir Edward Weary Dunlop Fellowship (G.A.M) and Lorenzo and Pamela Galli Charitable Trust (G.A.M).