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

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

doi:10.18632/oncotarget.10452

Cited by 98 publications

(147 citation statements)

References 84 publications

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“…THP-1 (p53null), SHI-1 (p53WT), and KG-1 (p53null) exhibited aberrant cell-cycle progression in response to CX-5461 with cells accumulating in late S and G2/M phase ( Figure 5A). In line with our recent study demonstrating CX-5461-mediated activation of ataxia telangiectasiamutated and Rad31-related kinase (ATM/ATR) signaling in the absence of global DNA damage in fibroblasts, 17 and consistent with aberrant G2/M transition, Pol I inhibition induced phosphorylation of the CHK1 on S345 and CHK2 threonine 68, which are ATM-/ATRdependent sites, respectively ( Figure 5B). Moreover, pharmacologic inhibition of ATM/ATR signaling partially rescued the delay in late S and the G2/M phase arrest in THP-1, SHI-1, and KG-1 cell lines ( Figure 5C-D).…”

Section: Cx-5461 Activates P53-independent Cell-cycle Checkpoint Signsupporting

confidence: 91%

“…These data, together with our previous studies, 8 demonstrate that acute inhibition of Pol I transcription leads to activation of multiple cell-cycle checkpoints 17 ; and specifically, a G1 checkpoint characterized by activation of p53 and a G2/M checkpoint associated with CHK1/ CHK2 signaling, downstream of ATM/ATR activation. Thus, mammalian cells appear to have evolved a number of mechanisms to monitor rRNA synthesis and inactivate cell-cycle progression if rRNA output does not match cellular demand.…”

Section: Discussionsupporting

confidence: 77%

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Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population

Hein

Cameron

Hannan

et al. 2017

Blood

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Key Points• Inhibition of RNA Pol I by CX-5461 treats aggressive AML and outperforms standard chemotherapy regimens.• CX-5461 induces p53-dependent apoptosis, p53-independent cell-cycle defects and differentiation, and reduces LICs.Despite the development of novel drugs, the prospects for many patients with acute myeloid leukemia (AML) remain dismal. This study reveals that the selective inhibitor of RNA polymerase I (Pol I) transcription, CX-5461, effectively treats aggressive AML, including mixed-lineage leukemia-driven AML, and outperforms standard chemotherapies. In addition to the previously characterized mechanism of action of CX-5461 (ie, the induction of p53-dependent apoptotic cell death), the inhibition of Pol I transcription also demonstrates potent efficacy in p53null AML in vivo. This significant survival advantage in both p53WT and p53null leukemic mice treated with CX-5461 is associated with activation of the checkpoint kinases 1/2, an aberrant G2/M cell-cycle progression and induction of myeloid differentiation of the leukemic blasts. The ability to target the leukemic-initiating cell population is thought to be essential for lasting therapeutic benefit. Most strikingly, the acute inhibition of Pol I transcription reduces both the leukemic granulocyte-macrophage progenitor and leukemia-initiating cell (LIC) populations, and suppresses their clonogenic capacity. This suggests that dysregulated Pol I transcription is essential for the maintenance of their leukemia-initiating potential. Together, these findings demonstrate the therapeutic utility of this new class of inhibitors to treat highly aggressive AML by targeting LICs. (Blood. 2017;129(21):2882-2895

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Section: Cx-5461 Activates P53-independent Cell-cycle Checkpoint Signsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 77%

Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population

Hein

Cameron

Hannan

et al. 2017

Blood

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“…While CX-5461 inhibits SL-1 interaction with Pol I and prevents Pol I recruitment to the rDNA promoter [56,57], it is also possible to inhibit Pol I transcription initiation…”

Section: Accepted Manuscript 20mentioning

confidence: 99%

“…Furthermore, we have recently demonstrated that acute treatment with CX-5461 (1 hour) induces chromatin defects at the rDNA associated with depletion of Pol I binding across the transcribed region, leading to activation of DNA damage signalling in the absence of global DNA damage [57]. Importantly, we reported improved therapeutic efficacy against lymphoma in vivo by combining CX-5461 with inhibitors of DNA damage signalling [57]. It is therefore likely that targeting Pol I transcription at multiple levels simultaneously (e.g., initiation / elongation and or rRNA processing) may further improve the efficacy of therapies targeting rDNA transcription.…”

Section: Accepted Manuscript 20mentioning

confidence: 99%

Cell cycle and growth stimuli regulate different steps of RNA polymerase I transcription

Hung

Lesmana

Peck

et al. 2017

Gene

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, Cell cycle and growth stimuli regulate different steps of RNA polymerase I transcription. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Gene(2016Gene( ), doi: 10.1016Gene( /j.gene.2016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT ACCEPTED MANUSCRIPT A C C E P T E D M A N U S C R I P T A C C E P T E D M A N U S C R I P T 3 AbstractTranscription of the ribosomal RNA genes (rDNA) by RNA Polymerase I (Pol I) is a major control step for ribosome synthesis and is tightly linked to cellular growth.However, the question of whether this process is modulated primarily at the level of transcription initiation or elongation is controversial. Studies in markedly different cell types have identified either initiation or elongation as the major control point. In this study, we have re-examined this question in NIH3T3 fibroblasts using a combination of metabolic labelling of the 47S rRNA, chromatin immunoprecipitation analysis of Pol I and overexpression of the transcription initiation factor Rrn3. Acute manipulation of growth factor levels altered rRNA synthesis rates over 8-fold without changing Pol I loading onto the rDNA. In fact, robust changes in Pol I loading were only observed under conditions where inhibition of rDNA transcription was associated with chronic serum starvation or cell cycle arrest. Overexpression of the transcription initiation factor Rrn3 increased loading of Pol I on the rDNA but failed to enhance rRNA synthesis in either serum starved, serum treated or G0/G1 arrested cells. Together these data suggest that transcription elongation is rate limiting for rRNA synthesis. We propose that transcription initiation is required for rDNA transcription in response to cell cycle cues, whereas elongation controls the dynamic range of rRNA synthesis output in response to acute growth factor modulation.

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“…While p53 dependent nucleolar stress is well understood, more recent research by Quin et al[73] has identified p53 independent mechanisms involving activation of ATM/ATR signalling which occurs without the induction of global DNA damage[73]. Evidently, ribosome biogenesis is a highly complex and finely balanced process involving multiple key effectors.…”

Section: Ribosome Biogenesismentioning

confidence: 99%

Advanced pancreatic ductal adenocarcinoma - Complexities of treatment and emerging therapeutic options

Diwakarla¹,

Hannan²,

Hein³

et al. 2017

WJG

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Pancreatic ductal adenocarcinoma is a devastating disease with a poor prognosis regardless of stage. To date the mainstay of therapy for advanced disease has been chemotherapy with little incremental improvements in outcome. Despite extensive research investigating new treatment options the current practices continue to utilise fluorouracil or gemcitabine containing combinations. The need for novel therapeutic approaches is mandated by the ongoing poor survival rates associated with this disease. One such approach may include manipulation of ribosome biogenesis and the nucleolar stress response, which has recently been applied to haematological malignancies such as lymphoma and prostate cancer with promising results. This review will focus on the current therapeutic options for pancreatic ductal adenocarcinoma and the complexities associated with developing novel treatments, with a particular emphasis on the role of the nucleolus as a treatment strategy.

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

Cited by 98 publications

References 84 publications

Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population

Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population

Cell cycle and growth stimuli regulate different steps of RNA polymerase I transcription

Advanced pancreatic ductal adenocarcinoma - Complexities of treatment and emerging therapeutic options

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