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Transcriptomic Analysis of TDP1-Knockout HEK293A Cells Treated with the TDP1 Inhibitor (Usnic Acid Derivative).
Alexandra L Zakharenko1, Nadezhda S Dyrkheeva1, Andrey V Markov1
1Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 8 Lavrentyeva Ave., 630090 Novosibirsk, Russia.
International Journal of Molecular Sciences
|October 16, 2025
Summary
Tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibition reduces cancer cell motility and alters gene expression. This TDP1 inhibitor potentiates topotecan
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- Tyrosyl-DNA phosphodiesterase 1 (TDP1) is crucial for repairing topoisomerase 1 (TOP1)-DNA complexes.
- TDP1 gene knockout in HEK293A cells provides a model for studying anticancer therapy mechanisms.
- Transcriptome analysis reveals gene expression changes in TDP1 knockout cells.
Purpose of the Study:
- To investigate the effect of a TDP1 inhibitor (OL9-119) and its combination with topotecan on the transcriptome of wild-type and TDP1 knockout HEK293A cells.
- To explore the potential antimetastatic effects of OL9-119 by analyzing its impact on gene expression related to cell motility.
- To identify genes affected by TDP1 inhibition, focusing on pathways like electron transport, mitochondrial function, and protein folding.
Main Methods:
- CRISPR/Cas9 gene editing to create TDP1 knockout HEK293A cells.
- Transcriptome analysis (RNA sequencing) to assess global gene expression changes.
- Treatment of wild-type and TDP1 knockout cells with a TDP1 inhibitor (OL9-119) and topotecan, individually and in combination.
Main Results:
- The TDP1 inhibitor OL9-119 reduced cell motility by downregulating specific genes, suggesting an antimetastatic potential.
- Transcriptome analysis revealed differentially expressed genes (DEGs) associated with electron transport, mitochondrial function, and protein folding upon TDP1 inhibition.
- OL9-119 demonstrated the ability to potentiate the antitumor effect of topotecan.
Conclusions:
- TDP1 inhibition by OL9-119 impacts cellular processes including motility, electron transport, mitochondrial function, and protein folding.
- OL9-119 exhibits potential as an antimetastatic agent and can enhance the efficacy of topotecan in cancer therapy.
- Understanding the transcriptome changes induced by TDP1 inhibition provides insights into therapeutic mechanisms and potential drug resistance pathways.
