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Carcinogenesis Advance Access originally published online on November 25, 2004
Carcinogenesis 2005 26(3):547-555; doi:10.1093/carcin/bgh347
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Carcinogenesis vol.26 no.3 © Oxford University Press 2004; all rights reserved.

ARTICLE

Incorporation of dUMP into DNA is a major source of spontaneous DNA damage, while excision of uracil is not required for cytotoxicity of fluoropyrimidines in mouse embryonic fibroblasts

Sonja Andersen2,*, Tina Heine3,*, Ragnhild Sneve2, Imbritt König2, Hans E. Krokan2, Bernd Epe3 and Hilde Nilsen1,4,5

1 Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire EN6 3LD, UK, 2 Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Medical Faculty, N-7489 Trondheim, Norway and 3 Institute of Pharmacy, University of Mainz, D-55099 Mainz, Germany

5 To whom correspondence should be addressed Email: hilde.nilsen{at}biotek.uio.no

Uracil may arise in DNA as a result of deamination of cytosine or through incorporation of dUMP instead of dTMP during replication. We have studied the steady-state levels of uracil in the DNA of primary cells and mouse embryonic fibroblast (MEF) cell lines from mice deficient in the Ung uracil-DNA glycosylase. The results show that the levels of uracil in the DNA of Ung–/– cells strongly depend on proliferation, indicating that the uracil residues originate predominantly from misincorporation during replication. Treatment with 5-fluoro-2'-deoxyuridine (5-FdUrd) or 5-fluorouracil (5-FU) gives rise to a dose-dependent increase of uracil in Ung–/– MEFs (up to 1.5-fold) but not in wild-type cells. Interestingly, Ung–/– MEFs accumulate AP-sites as well as uracil in response to 5-FdUrd but not to 5-FU. This accumulation of repair intermediates suggests a loss of tightly co-ordinated repair in the absence of Ung, and correlates with stronger inhibition of cell proliferation in response to 5-FdUrd, but not to 5-FU, in Ung–/– MEFs compared with wild-type cells. However, other cytotoxic effects of these fluoropyrimidines are comparable in both wild-type and Ung-deficient cells, demonstrating that excision of uracil from DNA by the Ung uracil-DNA glycosylase is not a prerequisite for obtaining cytotoxicity.


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