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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Halogenated thymidine analogues restore the expression of silenced genes without demethylation.

Transcriptional silencing of tumor suppressor genes by aberrant DNA methylation is a characteristic frequently observed in cancer cells. Therefore, reversing this process is a therapeutic target against cancer. In this study, we established a screening system for silencing inhibitors with cell lines transfected by a retroviral vector containing a luciferase gene. More than 100 nucleosides were tested for antisilencing activity with a selected clone in which the silenced expression of luciferase could be recovered by 5-aza-2'-deoxycytidine. A group of halogenated thymidine analogues was found to reactivate transcription of not only the reporter retrovirus vector but also endogenous glutathione-S-transferase 1 gene, without influence to DNA hypermethylation. Gel mobility shift assay showed that 5-bromo-2'-deoxyuridine (BrdUrd) or 5-iodo-2'-deoxyuridine incorporation did not affect the binding of the methyl-CpG binding protein motif to methylated DNA. Finally, in the retroviral promoter, BrdUrd treatment increased the acetylated histone H3 level and decreased methylation of histone H3 Lys9 in accordance with recovered transcription. This study shows that halogenated thymidines have an antisilencing effect without changing DNA methylation status by interfering with step(s) between DNA methylation and histone acetylation.[1]


  1. Halogenated thymidine analogues restore the expression of silenced genes without demethylation. Fan, J., Kodama, E., Koh, Y., Nakao, M., Matsuoka, M. Cancer Res. (2005) [Pubmed]
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