scholarly journals DNA intercalator BMH-21 inhibits RNA polymerase I independent of DNA damage response

Oncotarget ◽  
2014 ◽  
Vol 5 (12) ◽  
pp. 4361-4369 ◽  
Author(s):  
Laureen Colis ◽  
Karita Peltonen ◽  
Paul Sirajuddin ◽  
Hester Liu ◽  
Sara Sanders ◽  
...  
Keyword(s):  
Dna Damage ◽  
Rna Polymerase ◽  
Dna Damage Response ◽  
Rna Polymerase I ◽  
Dna Intercalator ◽  
Damage Response ◽  
Polymerase I

scholarly journals Targeting RNA Polymerase I transcription synergises with TOP1 inhibition in potentiating the DNA damage response in high-grade serous ovarian cancer

2019 ◽  
Author(s):  
Shunfei Yan ◽  
Piyush B. Madhamshettiwar ◽  
Kaylene J. Simpson ◽  
Sarah Ellis ◽  
Jian Kang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Rna Polymerase ◽  
Dna Damage Response ◽  
Parp Inhibitor ◽  
Rna Polymerase I ◽  
Serous Carcinoma ◽  
High Grade ◽  
Damage Response ◽  
Polymerase I

AbstractLimited effective therapeutic options are available for patients with recurrent high-grade serous carcinoma (HGSC), the most common histological subtype accounting for the majority of ovarian cancer deaths. We have shown efficacy in poly-ADP ribose polymerase (PARP) inhibitor-resistant HGSC for the RNA Polymerase I (Pol I) transcription inhibitor CX-5461 through its ability to activate a nucleolar-associated DNA damage response (DDR). Here, we screen the protein-coding genome to identify potential targets whose inhibition enhances the efficacy of CX-5461. We identify a network of cooperating inhibitory interactions, including components of homologous recombination (HR) DNA repair and DNA topoisomerase 1 (TOP1). We highlight that CX-5461 combined with topotecan, a TOP1 inhibitor used as salvage therapy in HGSC, induces robust cell cycle arrest and cell death in a panel of HR-proficient HGSC cell lines. The combination potentiates a nucleolar-associated DDR via recruitment of phosphorylated replication protein A (RPA) and ataxia telangiectasia and Rad3 related protein (ATR). CX-5461 plus low-dose topotecan cooperate to potently inhibit xenograft tumour growth, indicating the potential for this strategy to improve salvage therapeutic regimens to treat HGSC.

scholarly journals Inhibition of RNA Polymerase I Transcription Activates Targeted DNA Damage Response and Enhances the Efficacy of PARP Inhibitors in High-Grade Serous Ovarian Cancer

2019 ◽  
Author(s):  
Elaine Sanij ◽  
Katherine M. Hannan ◽  
Shunfei Yan ◽  
Jiachen Xuan ◽  
Jessica E. Ahern ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Parp Inhibitors ◽  
Rna Polymerase I ◽  
High Grade ◽  
Replication Forks ◽  
Serous Ovarian Cancer ◽  
Damage Response ◽  
Polymerase I

AbstractHigh-grade serous ovarian cancer (HGSOC) accounts for the majority of ovarian cancer and has a dismal prognosis. PARP inhibitors (PARPi) have revolutionized disease management of patients with homologous recombination (HR) DNA repair-deficient HGSOC. However, acquired resistance to PARPi by complex mechanisms including HR restoration and stabilisation of replication forks is a major challenge in the clinic. Here, we demonstrate CX-5461, an inhibitor of RNA polymerase I transcription of ribosomal RNA genes (rDNA), induces replication stress at rDNA leading to activation of DNA damage response and DNA damage involving MRE11-dependent degradation of replication forks. CX-5461 cooperates with PARPi in exacerbating DNA damage and enhances synthetic lethal interactions of PARPi with HR deficiency in HGSOC-patient-derived xenograft (PDX)in vivo. We demonstrate CX-5461 has a different sensitivity spectrum to PARPi and destabilises replication forks irrespective of HR pathway status, overcoming two well-known mechanisms of resistance to PARPi. Importantly, CX-5461 exhibits single agent efficacy in PARPi-resistant HGSOC-PDX. Further, we identify CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC. Therefore, CX-5461 is a promising therapy alone and in combination therapy with PARPi in HR-deficient HGSOC. CX-5461 is also an exciting treatment option for patients with relapsed HGSOC tumors that have poor clinical outcome.

scholarly journals Interferon Antagonist NSs of La Crosse Virus Triggers a DNA Damage Response-like Degradation of Transcribing RNA Polymerase II

2010 ◽  
Vol 286 (5) ◽  
pp. 3681-3692 ◽  
Author(s):  
Paul Verbruggen ◽  
Marius Ruf ◽  
Gjon Blakqori ◽  
Anna K. Överby ◽  
Martin Heidemann ◽  
...  
Keyword(s):  
Dna Damage ◽  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Dna Damage Response ◽  
La Crosse Virus ◽  
Damage Response

scholarly journals The chemotherapeutic agent CX-5461 irreversibly blocks RNA polymerase I initiation and promoter release to cause nucleolar disruption, DNA damage and cell inviability

NAR Cancer ◽  
2020 ◽  
Vol 2 (4) ◽  
Author(s):  
Jean-Clément Mars ◽  
Michel G Tremblay ◽  
Mélissa Valere ◽  
Dany S Sibai ◽  
Marianne Sabourin-Felix ◽  
...  
Keyword(s):  
Dna Damage ◽  
Rna Polymerase ◽  
Ribosomal Rna ◽  
Transcription Initiation ◽  
Ribosome Biogenesis ◽  
Chemotherapeutic Agent ◽  
Rna Polymerase I ◽  
Initiation Complex ◽  
Promoter Recruitment ◽  
Polymerase I

Abstract In the search for drugs to effectively treat cancer, the last 10 years have seen a resurgence of interest in targeting ribosome biogenesis. CX-5461 is a potential inhibitor of ribosomal RNA synthesis that is now showing promise in phase I trials as a chemotherapeutic agent for a range of malignancies. Here, we show that CX-5461 irreversibly inhibits ribosomal RNA transcription by arresting RNA polymerase I (RPI/Pol1/PolR1) in a transcription initiation complex. CX-5461 does not achieve this by preventing formation of the pre-initiation complex nor does it affect the promoter recruitment of the SL1 TBP complex or the HMGB-box upstream binding factor (UBF/UBTF). CX-5461 also does not prevent the subsequent recruitment of the initiation-competent RPI–Rrn3 complex. Rather, CX-5461 blocks promoter release of RPI–Rrn3, which remains irreversibly locked in the pre-initiation complex even after extensive drug removal. Unexpectedly, this results in an unproductive mode of RPI recruitment that correlates with the onset of nucleolar stress, inhibition of DNA replication, genome-wide DNA damage and cellular senescence. Our data demonstrate that the cytotoxicity of CX-5461 is at least in part the result of an irreversible inhibition of RPI transcription initiation and hence are of direct relevance to the design of improved strategies of chemotherapy.

scholarly journals A DNA Damage Response System Associated with the phosphoCTD of Elongating RNA Polymerase II

PLoS ONE ◽  
2013 ◽  
Vol 8 (4) ◽  
pp. e60909 ◽  
Author(s):  
Tiffany Sabin Winsor ◽  
Bartlomiej Bartkowiak ◽  
Craig B. Bennett ◽  
Arno L. Greenleaf
Keyword(s):  
Dna Damage ◽  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Dna Damage Response ◽  
Response System ◽  
Damage Response

scholarly journals Coilin participates in the suppression of RNA polymerase I in response to cisplatin-induced DNA damage

2011 ◽  
Vol 22 (7) ◽  
pp. 1070-1079 ◽  
Author(s):  
Andrew S. Gilder ◽  
Phi M. Do ◽  
Zunamys I Carrero ◽  
Angela M. Cosman ◽  
Hanna J. Broome ◽  
...  
Keyword(s):  
Dna Damage ◽  
Rna Polymerase ◽  
Rna Polymerase I ◽  
Rrna Synthesis ◽  
Γ Irradiation ◽  
Small Nuclear Ribonucleoprotein ◽  
Pol I ◽  
Upstream Binding Factor ◽  
Polymerase I ◽  
Nuclear Ribonucleoprotein

Coilin is a nuclear phosphoprotein that concentrates within Cajal bodies (CBs) and impacts small nuclear ribonucleoprotein (snRNP) biogenesis. Cisplatin and γ-irradiation, which cause distinct types of DNA damage, both trigger the nucleolar accumulation of coilin, and this temporally coincides with the repression of RNA polymerase I (Pol I) activity. Knockdown of endogenous coilin partially overrides the Pol I transcriptional arrest caused by cisplatin, while both ectopically expressed and exogenous coilin accumulate in the nucleolus and suppress rRNA synthesis. In support of this mechanism, we demonstrate that both cisplatin and γ-irradiation induce the colocalization of coilin with RPA-194 (the largest subunit of Pol I), and we further show that coilin can specifically interact with RPA-194 and the key regulator of Pol I activity, upstream binding factor (UBF). Using chromatin immunoprecipitation analysis, we provide evidence that coilin modulates the association of Pol I with ribosomal DNA. Collectively, our data suggest that coilin acts to repress Pol I activity in response to cisplatin-induced DNA damage. Our findings identify a novel and unexpected function for coilin, independent of its role in snRNP biogenesis, establishing a new link between the DNA damage response and the inhibition of rRNA synthesis.

Dynamic Behavior of the RNA Polymerase II and the Ubiquitin Proteasome System During the Neuronal DNA Damage Response to Ionizing Radiation

2015 ◽  
Vol 53 (10) ◽  
pp. 6799-6808 ◽  
Author(s):  
Iñigo Casafont ◽  
Ana Palanca ◽  
Vanesa Lafarga ◽  
Jorge Mata-Garrido ◽  
Maria T. Berciano ◽  
...  
Keyword(s):  
Dna Damage ◽  
Ionizing Radiation ◽  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Dynamic Behavior ◽  
Dna Damage Response ◽  
Ubiquitin Proteasome System ◽  
Damage Response ◽  
Ubiquitin Proteasome

scholarly journals Trypanosoma brucei ATR Links DNA Damage Signaling during Antigenic Variation with Regulation of RNA Polymerase I-Transcribed Surface Antigens

Cell Reports ◽  
2020 ◽  
Vol 30 (3) ◽  
pp. 836-851.e5 ◽  
Author(s):  
Jennifer Ann Black ◽  
Kathryn Crouch ◽  
Leandro Lemgruber ◽  
Craig Lapsley ◽  
Nicholas Dickens ◽  
...  
Keyword(s):  
Dna Damage ◽  
Rna Polymerase ◽  
Trypanosoma Brucei ◽  
Antigenic Variation ◽  
Surface Antigens ◽  
Rna Polymerase I ◽  
Dna Damage Signaling ◽  
Polymerase I
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