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Chromatin damage generated by DNA intercalators leads to degradation of RNA Polymerase II.

Authors :
Espinoza JA
Kanellis DC
Saproo S
Leal K
Martinez JF
Bartek J
Lindström MS
Source :
Nucleic acids research [Nucleic Acids Res] 2024 May 08; Vol. 52 (8), pp. 4151-4166.
Publication Year :
2024

Abstract

In cancer therapy, DNA intercalators are mainly known for their capacity to kill cells by inducing DNA damage. Recently, several DNA intercalators have attracted much interest given their ability to inhibit RNA Polymerase I transcription (BMH-21), evict histones (Aclarubicin) or induce chromatin trapping of FACT (Curaxin CBL0137). Interestingly, these DNA intercalators lack the capacity to induce DNA damage while still retaining cytotoxic effects and stabilize p53. Herein, we report that these DNA intercalators impact chromatin biology by interfering with the chromatin stability of RNA polymerases I, II and III. These three compounds have the capacity to induce degradation of RNA polymerase II and they simultaneously enable the trapping of Topoisomerases TOP2A and TOP2B on the chromatin. In addition, BMH-21 also acts as a catalytic inhibitor of Topoisomerase II, resembling Aclarubicin. Moreover, BMH-21 induces chromatin trapping of the histone chaperone FACT and propels accumulation of Z-DNA and histone eviction, similarly to Aclarubicin and CBL0137. These DNA intercalators have a cumulative impact on general transcription machinery by inducing accumulation of topological defects and impacting nuclear chromatin. Therefore, their cytotoxic capabilities may be the result of compounding deleterious effects on chromatin homeostasis.<br /> (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Details

Language :
English
ISSN :
1362-4962
Volume :
52
Issue :
8
Database :
MEDLINE
Journal :
Nucleic acids research
Publication Type :
Academic Journal
Accession number :
38340348
Full Text :
https://doi.org/10.1093/nar/gkae069