Inhibition of RNA polymerase I transcription initiation by CX-5461 activates non-canonical ATM/ATR signaling
Number of Authors: 20
2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 31, 49800-49818 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2016. Vol. 7, no 31, 49800-49818 p.
RNA polymerase I, rDNA, CX-5461, nucleolar stress response, DNA damage signaling
Cell Biology Cell and Molecular Biology
IdentifiersURN: urn:nbn:se:su:diva-135980DOI: 10.18632/oncotarget.10452ISI: 000385422000078OAI: oai:DiVA.org:su-135980DiVA: diva2:1050362