Base Excision by Thymine DNA Glycosylase Mediates DNA-Directed Cytotoxicity of 5-Fluorouracil
- Journal Article
Rights / licenseCreative Commons Attribution 3.0 Unported
5-Fluorouracil (5-FU) has been used in clinical cancer therapy for more than four decades. Despite a moderate response rate and a high propensity of tumors to develop resistance to the drug, 5-FU remains a mainstay in the first-line treatment of colorectal cancer in particular. But precisely how 5-FU kills cancerous cells is not well understood. It is known, for example, that 5-FU affects RNA or DNA metabolism. Its DNA-directed cytotoxicity is thought to be based on extensive misincorporation of uracil and 5-FU into cellular DNA, and it has been proposed that the excision of these bases by uracil DNA glycosylases (UDGs) results in destructive DNA fragmentation, which can ultimately lead to cell death. However, the UDG responsible has not been identified. We now show that inactivation of only one of four mammalian UDGs, the thymine DNA glycosylase (TDG) in mouse and human cells is sufficient to confer resistance to 5-FU, whereas overexpression of TDG sensitizes cells to the drug. We provide further experimental evidence to show that excision of 5-FU from DNA by TDG, but not by other UDGs, inhibits efficient downstream processing of the lesion. This leads to an accumulation of DNA repair intermediates, which induce DNA damage signaling and, eventually, cell death. Thus, TDG activity in cells represents an important determinant of the DNA-directed cytotoxicity of 5-FU, an observation that might help us to understand the variable response to 5-FU treatments in cancer. Show more
Journal / seriesPLoS Biology
Pages / Article No.
PublisherPublic Library of Science
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