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) |
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UniBasel Contributors: | Kunz, Christophe and Schürmann, David and Focke, Frauke and Schär, Primo Leo |
Item Type: | Article, refereed |
Article Subtype: | Research Article |
Publisher: | Public Library of Science |
ISSN: | 1545-7885 |
Note: | Publication type according to Uni Basel Research Database: Journal article |
Related URLs: | |
Identification Number: |
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Last Modified: | 24 May 2013 09:00 |
Deposited On: | 22 Mar 2012 13:32 |
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