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Inhibition of RNA p...
Inhibition of RNA polymerase I transcription initiation by CX-5461 activates non-canonical ATM/ATR signaling
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- Quin, Jaclyn (author)
- Stockholms universitet,Institutionen för molekylär biovetenskap, Wenner-Grens institut,Peter MacCallum Cancer Centre, Australia; University of Melbourne, Australia
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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 (author)
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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 (author)
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Hannan, Ross D. (author)
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(creator_code:org_t)
- 2016-07-06
- 2016
- English.
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In: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:31, s. 49800-49818
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https://doi.org/10.1...
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Abstract
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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.
Subject headings
- NATURVETENSKAP -- Biologi -- Cellbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Cell Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Keyword
- RNA polymerase I
- rDNA
- CX-5461
- nucleolar stress response
- DNA damage signaling
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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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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show more...
-
Ahern, Jessica
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Khot, Amit
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Hein, Nadine
-
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
-
Johnstone, Ricky ...
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Drygin, Denis
-
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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show less...
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Cell Biology
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Cell and Molecul ...
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Oncotarget
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Stockholm University