Attenuated DNA Damage Repair by Trichostatin A through BRCA1 Suppression
| Autor: | Yin Zhang, Alexandre Dimtchev, Theresa Carr, Mira Jung, Naghmeh Zaer, Anatoly Dritschilo |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
DNA Replication
DNA Repair DNA damage Biophysics Down-Regulation Apoptosis Biology Hydroxamic Acids Histones Radiation sensitivity Cell Line Tumor Radioresistance medicine Humans Radiology Nuclear Medicine and imaging Cell Nucleus Radiation BRCA1 Protein DNA replication DNA Molecular biology Rad52 DNA Repair and Recombination Protein Squamous carcinoma Comet assay Trichostatin A Cancer research Histone deacetylase DNA Damage medicine.drug |
| Zdroj: | Radiation Research. 168:115-124 |
| ISSN: | 1938-5404 0033-7587 |
| Popis: | Recent studies have demonstrated that some histone deacetylase (HDAC) inhibitors enhance cellular radiation sensitivity. However, the underlying mechanism for such a radiosensitizing effect remains unexplored. Here we show evidence that treatment with the HDAC inhibitor trichostatin A (TSA) impairs radiation-induced repair of DNA damage. The effect of TSA on the kinetics of DNA damage repair was measured by performing the comet assay and gamma-H2AX focus analysis in radioresistant human squamous carcinoma cells (SQ-20B). TSA exposure increased the amount of radiation-induced DNA damage and slowed the repair kinetics. Gene expression profiling also revealed that a majority of the genes that control cell cycle, DNA replication and damage repair processes were down-regulated after TSA exposure, including BRCA1. The involvement of BRCA1 was further demonstrated by expressing ectopic wild-type BRCA1 in a BRCA1 null cell line (HCC-1937). TSA treatment enhanced radiation sensitivity of HCC-1937/wtBRCA1 clonal cells, which restored cellular radiosensitivity (D(0) = 1.63 Gy), to the control level (D(0) = 1.03 Gy). However, TSA had no effect on the level of radiosensitivity of BRCA1 null cells. Our data demonstrate for the first time that TSA treatment modulates the radiation-induced DNA damage repair process, in part by suppressing BRCA1 gene expression, suggesting that BRCA1 is one of molecular targets of TSA. |
| Databáze: | OpenAIRE |
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