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Inhibition of RNA p...
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Quin, JaclynStockholms universitet,Institutionen för molekylär biovetenskap, Wenner-Grens institut,Peter MacCallum Cancer Centre, Australia; University of Melbourne, Australia
(author)
Inhibition of RNA polymerase I transcription initiation by CX-5461 activates non-canonical ATM/ATR signaling
- Article/chapterEnglish2016
Publisher, publication year, extent ...
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2016-07-06
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Impact Journals, LLC,2016
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printrdacarrier
Numbers
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LIBRIS-ID:oai:DiVA.org:su-135980
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https://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-135980URI
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https://doi.org/10.18632/oncotarget.10452DOI
Supplementary language notes
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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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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Chan, Keefe T.
(author)
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Devlin, Jennifer R.
(author)
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Cameron, Donald P.
(author)
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Diesch, Jeannine
(author)
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Cullinane, Carleen
(author)
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Ahern, Jessica
(author)
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Khot, Amit
(author)
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Hein, Nadine
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George, Amee J.
(author)
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Hannan, Katherine M.
(author)
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Poortinga, Gretchen
(author)
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Sheppard, Karen E.
(author)
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Khanna, Kum Kum
(author)
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Johnstone, Ricky W.
(author)
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Drygin, Denis
(author)
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McArthur, Grant A.
(author)
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Pearson, Richard B.
(author)
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Sanij, Elaine
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Hannan, Ross D.
(author)
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Stockholms universitetInstitutionen för molekylär biovetenskap, Wenner-Grens institut
(creator_code:org_t)
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In:Oncotarget: Impact Journals, LLC7:31, s. 49800-498181949-2553
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Quin, Jaclyn
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Chan, Keefe T.
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Devlin, Jennifer ...
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Cameron, Donald ...
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Diesch, Jeannine
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Cullinane, Carle ...
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Ahern, Jessica
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Khot, Amit
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Hein, Nadine
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George, Amee J.
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Hannan, Katherin ...
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Poortinga, Gretc ...
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Sheppard, Karen ...
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Khanna, Kum Kum
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Johnstone, Ricky ...
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Drygin, Denis
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McArthur, Grant ...
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Pearson, Richard ...
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Sanij, Elaine
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Hannan, Ross D.
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Stockholm University