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Evidence of a reduced DNA topoisomerase II mRNA expression after ionizing radiation
F Goldwasser1, I Bae, Y Pommier
1Division of Basic Sciences, National Cancer Institute, National Institute of Health, Bethesda, Maryland, USA. F. Goldwasser@wanadoo.fr
Abstract:
DNA topoisomerase II (top2) is a nuclear enzyme which resolves the topological constraints during DNA metabolism and is the target of some of the most active drugs used in cancer chemotherapy. Top2 is regulated both transcriptionally and post-transcriptionally and its expression is coupled to cell cycle position. To explore the regulation of top2 after DNA damage, we studied the behavior of cell lines of the National Cancer Institute Anticancer Drug Screen, previously characterized for p53 status, in response to ionizing radiation. The kinetics of top2 mRNA expression were measured using quantitative hybridization. A profound and transient decrease of top2 mRNA after irradiation was detected within four hours in 30% of the 25 cell lines tested. This transient top2 decrease in mRNA expression occurred independently of the p53 status of the cell lines and was not associated with increased apoptotic DNA fragmentation. This observation indicates that a transient decrease in top2 mRNA expression may occur after DNA damage and suggests the need for preferential schedule when planning the use of top2 inhibitors with ionizing radiation during combined radio-chemotherapy treatments.
Insights
Ionizing radiation causes a temporary drop in DNA topoisomerase II (top2) mRNA levels in many cancer cell lines. This finding is crucial for optimizing combined radio-chemotherapy treatments targeting top2.
Area of Science:
- Molecular Biology
- Cancer Research
- Genomics
Background:
- DNA topoisomerase II (top2) is a critical nuclear enzyme involved in DNA metabolism and a key target for cancer chemotherapy.
- Top2 activity and expression are tightly regulated throughout the cell cycle and can be influenced by various factors.
Purpose of the Study:
- To investigate the regulation of DNA topoisomerase II (top2) mRNA expression following DNA damage induced by ionizing radiation.
- To determine if p53 status influences the response of top2 mRNA levels to DNA damage.
Main Methods:
- Utilized a panel of National Cancer Institute cell lines with known p53 status.
- Quantified top2 mRNA expression kinetics using quantitative hybridization after exposure to ionizing radiation.
Main Results:
- A significant, transient decrease in top2 mRNA was observed within four hours in approximately 30% of the tested cell lines post-irradiation.
- This downregulation of top2 mRNA occurred independently of the cell lines' p53 status.
- The observed decrease in top2 mRNA was not correlated with increased apoptotic DNA fragmentation.
Conclusions:
- DNA damage induced by ionizing radiation can lead to a transient decrease in top2 mRNA expression.
- This transient downregulation suggests a need for careful scheduling of topoisomerase II inhibitors when used in combination with ionizing radiation for cancer therapy.