CX-5461 Preferentially Induces Top2α-Dependent DNA Breaks at Ribosomal DNA Loci
- Author(s)
- Cameron, DP; Sornkom, J; Alsahafi, S; Drygin, D; Poortinga, G; McArthur, GA; Hein, N; Hannan, R; Panov, KI;
- Details
- Publication Year 2024-07-08,Volume 12,Issue #7,Page 1514
- Journal Title
- Biomedicines
- Publication Type
- Research article
- Abstract
- While genotoxic chemotherapeutic agents are among the most effective tools to combat cancer, they are often associated with severe adverse effects caused by indiscriminate DNA damage in non-tumor tissue as well as increased risk of secondary carcinogenesis. This study builds on our previous work demonstrating that the RNA Polymerase I (Pol I) transcription inhibitor CX-5461 elicits a non-canonical DNA damage response and our discovery of a critical role for Topoisomerase 2α (Top2α) in the initiation of Pol I-dependent transcription. Here, we identify Top2α as a mediator of CX-5461 response in the murine Eµ-Myc B lymphoma model whereby sensitivity to CX-5461 is dependent on cellular Top2α expression/activity. Most strikingly, and in contrast to canonical Top2α poisons, we found that the Top2α-dependent DNA damage induced by CX-5461 is preferentially localized at the ribosomal DNA (rDNA) promoter region, thereby highlighting CX-5461 as a loci-specific DNA damaging agent. This mechanism underpins the efficacy of CX-5461 against certain types of cancer and can be used to develop effective non-genotoxic anticancer drugs.
- Publisher
- MDPI
- Keywords
- Cx-5461; DNA damage pathway; RNA Polymerase I; double-strand breaks; nucleolar surveillance pathway; p53; ribosome biogenesis; topoisomerase
- Department(s)
- Laboratory Research
- Publisher's Version
- https://doi.org/10.3390/biomedicines12071514
- Open Access at Publisher's Site
https://doi.org/10.3390/biomedicines12071514- Terms of Use/Rights Notice
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Creation Date: 2024-08-29 01:38:13
Last Modified: 2024-08-29 01:48:55