CX-5461 Preferentially Induces Top2α-Dependent DNA Breaks at Ribosomal DNA Loci
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
Open Access at Publisher's Site
https://doi.org/10.3390/biomedicines12071514
Terms of Use/Rights Notice
Refer to copyright notice on published article.


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