Inhibition of RNA polymerase I transcription initiation by CX-5461 activates non-canonical ATM/ATR signaling
| Autor: | Amit Khot, Amee J George, Ross D. Hannan, Kum Kum Khanna, Carleen Cullinane, Karen E. Sheppard, Elaine Sanij, Denis Drygin, Jessica E. Ahern, Katherine M. Hannan, Nadine Hein, Richard B. Pearson, Grant A. McArthur, Jeannine Diesch, Ricky W. Johnstone, Donald P. Cameron, Keefe T. Chan, Jaclyn E Quin, Gretchen Poortinga, Jennifer R. Devlin |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cell cycle checkpoint Nucleolus rDNA Ribosome biogenesis Apoptosis RNA polymerase I Ataxia Telangiectasia Mutated Proteins Cell Enlargement Biology DNA damage signaling DNA Ribosomal Mice 03 medical and health sciences chemistry.chemical_compound Animals Humans CX-5461 Benzothiazoles Naphthyridines Cell Proliferation Nucleic Acid Synthesis Inhibitors Genetics Fibroblasts Cell cycle Chromatin 3. Good health Cell biology Mice Inbred C57BL 030104 developmental biology Oncology chemistry Hematologic Neoplasms nucleolar stress response Comet Assay Tumor Suppressor Protein p53 Signal transduction Cell Nucleolus DNA DNA Damage Signal Transduction Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.10452 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|