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Base excision by thymine DNA glycosylase mediates DNA-directed cytotoxicity of 5-fluorouracil

Kunz, Christophe and Focke, Frauke and Saito, Yusuke and Schuermann, David and Lettieri, Teresa and Selfridge, Jim and Schär, Primo. (2009) Base excision by thymine DNA glycosylase mediates DNA-directed cytotoxicity of 5-fluorouracil. PLoS Biology, Vol. 7, H. 4 , e91.

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Official URL: http://edoc.unibas.ch/dok/A5253991

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Abstract

5-Fluorouracil (5-FU), a chemotherapeutic drug commonly used in cancer treatment, imbalances nucleotide pools, thereby favoring misincorporation of uracil and 5-FU into genomic DNA. The processing of these bases by DNA repair activities was proposed to cause DNA-directed cytotoxicity, but the underlying mechanisms have not been resolved. In this study, we investigated a possible role of thymine DNA glycosylase (TDG), one of four mammalian uracil DNA glycosylases (UDGs), in the cellular response to 5-FU. Using genetic and biochemical tools, we found that inactivation of TDG significantly increases resistance of both mouse and human cancer cells towards 5-FU. We show that excision of DNA-incorporated 5-FU by TDG generates persistent DNA strand breaks, delays S-phase progression, and activates DNA damage signaling, and that the repair of 5-FU-induced DNA strand breaks is more efficient in the absence of TDG. Hence, excision of 5-FU by TDG, but not by other UDGs (UNG2 and SMUG1), prevents efficient downstream processing of the repair intermediate, thereby mediating DNA-directed cytotoxicity. The status of TDG expression in a cancer is therefore likely to determine its response to 5-FU-based chemotherapy.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Division of Biochemistry and Genetics
03 Faculty of Medicine > Departement Biomedizin > Division of Biochemistry and Genetics > Molecular Genetics (Schär)
UniBasel Contributors:Kunz, Christophe and Schürmann, David and Focke, Frauke and Schär, Primo Leo
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Public Library of Science
ISSN:1545-7885
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:24 May 2013 09:00
Deposited On:22 Mar 2012 13:32

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