Base excision by thymine DNA glycosylase mediates DNA-directed cytotoxicity of 5-fluorouracil.
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 underl...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2009-04-01
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| Series: | PLoS Biology |
| Online Access: | http://europepmc.org/articles/PMC2671560 |
| _version_ | 1819153478840221696 |
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| author | Christophe Kunz Frauke Focke Yusuke Saito David Schuermann Teresa Lettieri Jim Selfridge Primo Schär |
| author_facet | Christophe Kunz Frauke Focke Yusuke Saito David Schuermann Teresa Lettieri Jim Selfridge Primo Schär |
| author_sort | Christophe Kunz |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T15:05:50Z |
| format | Article |
| id | doaj.art-4165cec158c9407b8bacefe22d778183 |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-12-22T15:05:50Z |
| publishDate | 2009-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-4165cec158c9407b8bacefe22d7781832022-12-21T18:22:00ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852009-04-0174e9110.1371/journal.pbio.1000091Base excision by thymine DNA glycosylase mediates DNA-directed cytotoxicity of 5-fluorouracil.Christophe KunzFrauke FockeYusuke SaitoDavid SchuermannTeresa LettieriJim SelfridgePrimo Schär5-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.http://europepmc.org/articles/PMC2671560 |
| spellingShingle | Christophe Kunz Frauke Focke Yusuke Saito David Schuermann Teresa Lettieri Jim Selfridge Primo Schär Base excision by thymine DNA glycosylase mediates DNA-directed cytotoxicity of 5-fluorouracil. PLoS Biology |
| title | Base excision by thymine DNA glycosylase mediates DNA-directed cytotoxicity of 5-fluorouracil. |
| title_full | Base excision by thymine DNA glycosylase mediates DNA-directed cytotoxicity of 5-fluorouracil. |
| title_fullStr | Base excision by thymine DNA glycosylase mediates DNA-directed cytotoxicity of 5-fluorouracil. |
| title_full_unstemmed | Base excision by thymine DNA glycosylase mediates DNA-directed cytotoxicity of 5-fluorouracil. |
| title_short | Base excision by thymine DNA glycosylase mediates DNA-directed cytotoxicity of 5-fluorouracil. |
| title_sort | base excision by thymine dna glycosylase mediates dna directed cytotoxicity of 5 fluorouracil |
| url | http://europepmc.org/articles/PMC2671560 |
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