5-Fluorouracil Incorporated into DNA Is Excised by the Smug1 DNA Glycosylase to Reduce Drug Cytotoxicity
Abstract
5-Fluorouracil (FU) has been widely used for more than four decades in the treatment of a range of common cancers. The fluorine-substituted uracila analogue is converted to several active metabolites but the mechanism of cytotoxicity has remained unclear. In a widely cited but unsubstantiated model, FU is thought to kill cells via the inhibition of thymidylate synthase and increased use of dUTP in place of TTP during DNA replication, with subsequent excision of high levels of uracil causing the fragmentation of newly synthesized DNA. Using gene-targeted cell lines defective in one or both of the two mammalian uracil-DNA glycosylase repair enzymes, we were able to test this model of FU cytotoxicity. Here, we show that incorporation of FU itself into DNA has been previously underestimated and is a predominant cause of cytotoxicity. FU readily becomes incorporated into the DNA of drug-treated cells, and accumulation of FU in the genome, rather than uracil excision, is correlated with FU cytotoxicity in mammalian cells. Furthermore, the Smug1, but not the Ung, uracil-DNA glycosylase excises FU from DNA and protects against cell killing. The data provides a clearer understanding of the action of FU, suggesting predictive biomarkers of drug response and a mechanism for acquired resistance in tumors. [Cancer Res 2007;67(3):940–5]
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
FdU may be removed by the uracil glycosylase Smug1, protecting cells from death.
“FdU may be excised by the uracil glycosylase Smug1 to protect cells from death [210, 211]”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [211]
MutSα recognizes and binds FdU:G mismatch pairs in an in vitro binding assay.
“MutSα recognizes and associates with FdU:G mismatch pairs in an in vitro binding experiment”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [211]
Cites
5-Fluorouracil: mechanisms of action and clinical strategies
Longley, D. B., Harkin, D. P., & Johnston, P. G. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1074 · Cited by 5,332 · see citing works
miRBase: microRNA sequences, targets and gene nomenclature
Griffiths‐Jones, S. (2005) · Nucleic Acids Research · doi:10.1093/nar/gkj112 · Cited by 4,713 · see citing works
Fluorinated pyrimidines, a new class of tumour-inhibitory compounds
HEIDELBERGER, C., CHAUDHURI, N. K., DANNEBERG, P., MOOREN, D., GRIESBACH, L., DUSCHINSKY, R., SCHNITZER, R. J., PLEVEN, E., & SCHEINER, J. (1957) · Nature · doi:10.1038/179663a0 · Cited by 1,603 · see citing works
Miwa, M., Ura, M., Nishida, M., Sawada, N., Ishikawa, T., Mori, K., Shimma, N., UMEDA, I., & Ishitsuka, H. (1998) · European Journal of Cancer · doi:10.1016/s0959-8049(98)00058-6 · Cited by 1,239 · see citing works
Salonga, D. S., Danenberg, K. D., Johnson, M. R., Metzger, R., Groshen, S. G., Tsao-Wei, D. D., Lenz, H.-J., Leichman, C. G., Leichman, L., Diasio, R. B., et al. (2000) · PubMed · Cited by 829 · see citing works
INTERACTIONS BETWEEN DEOXYRIBONUCLEOTIDE AND DNA SYNTHESIS
Reichard, P. A. (1988) · Annual Review of Biochemistry · doi:10.1146/annurev.bi.57.070188.002025 · Cited by 773 · see citing works
Induction of thymidylate synthase as a 5-fluorouracil resistance mechanism
Peters, G. J., Backus, H. H. J., Freemantle, S., van Triest, B., Codacci-Pisanelli, G., van der Wilt, C. L., Smid, K., Lunec, J., Calvert, H., Marsh, S., et al. (2002) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/s0925-4439(02)00082-0 · Cited by 419 · see citing works
Kavli, B., Sundheim, O., Akbari, M., Otterlei, M., Nilsen, H. L., Skorpen, F., Aas, P. A., Hagen, L., Krokan, H. E., & Slupphaug, G. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m207107200 · Cited by 346 · see citing works
Nilsen, H. L., Rosewell, I. R., Robins, P., Skjelbred, C. F., Andersen, S. B., Slupphaug, G., Daly, G., Krokan, H. E., Lindahl, T. L., & Barnes, D. E. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)80271-3 · Cited by 320 · see citing works
Self-citationNilsen, H. L., Otterlei, M., Haug, T., Steinsbekk, K. S., Hernes, T. A. N., Skorpen, F., & Krokan, H. E. (1997) · Nucleic Acids Research · doi:10.1093/nar/25.4.750 · Cited by 314 · see citing works
Noordhuis, P., Holwerda, U., van der Wilt, C. L., et al. (2004) · Annals of Oncology · doi:10.1093/annonc/mdh264 · Cited by 263 · see citing works
Rich, T. A., Shepard, R. C., & Mosley, S. T. (2004) · Journal of Clinical Oncology · doi:10.1200/jco.2004.08.009 · Cited by 213 · see citing works
Excision of deaminated cytosine from the vertebrate genome: role of the SMUG1 uracil–DNA glycosylase
Nilsen, H. L., Haushalter, K. A., Robins, P., Barnes, D. E., Verdine, G. L., & Lindahl, T. L. (2001) · The EMBO Journal · doi:10.1093/emboj/20.15.4278 · Cited by 196 · see citing works
Self-citationPeters, G. J., Laurensse, E. J., LEYVA, A., et al. (1986) · PubMed · Cited by 193 · see citing works
Hardeland, U. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkg344 · Cited by 149 · see citing works
Structure and Specificity of the Vertebrate Anti-Mutator Uracil-DNA Glycosylase SMUG1
Wibley, J., Waters, T. R., Haushalter, K. A., Verdine, G. L., & Pearl, L. H. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00235-1 · Cited by 143 · see citing works
Linking uracil base excision repair and 5-fluorouracil toxicity in yeast
Seiple, L. A. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkj430 · Cited by 127 · see citing works
DNA base excision repair of uracil residues in reconstituted nucleosome core particles
Nilsen, H. L., Lindahl, T. L., & Verreault, A. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf581 · Cited by 127 · see citing works
Self-citationCortellino, S., Turner, D. P., Masciullo, V., Schepis, F., Albino, D., Daniel, R., Skalka, A. M., Meropol, N. J., Alberti, C., Larue, L., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2334585100 · Cited by 127 · see citing works
Mechanistic and Predictive Profiling of 5-Fluorouracil Resistance in Human Cancer Cells
Wang, W., Cassidy, J., O’Brien, V., Ryan, K. M., & Collie-Duguid, E. S. R. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-0970 · Cited by 120 · see citing works
Andersen, S. B. (2004) · Carcinogenesis · doi:10.1093/carcin/bgh347 · Cited by 111 · see citing works
An, Q., Robins, P., Lindahl, T. L., & Barnes, D. E. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600689 · Cited by 108 · see citing works
Self-citationSchuetz, J. D., Wallace, H., & Diasio, R. B. (1984) · PubMed · Cited by 105 · see citing works
5-Fluoro-2'-deoxyuridine incorporation in L1210 DNA.
Kufe, D. W., Major, P. P., Egan, E. M., et al. (1981) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)52479-6 · Cited by 102 · see citing works
Caradonna, S. J., & Cheng, Y. (1980) · PubMed · Cited by 93 · see citing works
Ingraham, H. A., Tseng, B., & Goulian, M. (1982) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)14573-2 · Cited by 89 · see citing works
Canman, C. E., Radany, E. H., Parsels, L. A., et al. (1994) · PubMed · Cited by 83 · see citing works
Koehler, S. E., & Ladner, R. D. (2004) · Molecular Pharmacology · doi:10.1016/s0026-895x(24)05645-1 · Cited by 80 · see citing works
Sowers, L. C., Eritja, R., Kaplan, B., Goodman, M. F., & Fazakerly, G. V. (1988) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)68108-6 · Cited by 77 · see citing works
A role for DNA mismatch repair in sensing and responding to fluoropyrimidine damage
Meyers, M., Hwang, A., Wagner, M. W., Bruening, A. J., Veigl, M. L., Sedwick, W. D., & Boothman, D. A. (2003) · Oncogene · doi:10.1038/sj.onc.1206941 · Cited by 70 · see citing works
Pu, W. T., & Struhl, K. (1992) · Nucleic Acids Research · doi:10.1093/nar/20.4.771 · Cited by 66 · see citing works
Structural and dynamic properties of a fluorouracil-adenine base pair in DNA studied by proton NMR.
Sowers, L. C., Eritja, R., Kaplan, B. E., et al. (1987) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)47745-9 · Cited by 39 · see citing works
Mechanisms of excision of 5-fluorouracil by uracil DNA glycosylase in normal human cells.
Mauro, D. J., de Riel, J. K., Tallarida, R. J., et al. (1993) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)13666-3 · Cited by 38 · see citing works
Welsh, S. J., Hobbs, S., & Aherne, G. W. (2003) · European Journal of Cancer · doi:10.1016/s0959-8049(02)00610-x · Cited by 36 · see citing works
Habener, J. F., Vo�, C., Le, D. B., et al. (1988) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.85.6.1735 · Cited by 32 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
5-fluorouracil and other fluoropyrimidines in colorectal cancer: Past, present and future
Vodenkova, S., Buchler, T., Cervena, K., Veskrnova, V., Vodicka, P., & Vymetalkova, V. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.107447 · Cited by 956 · see citing works
DNA glycosylases: In DNA repair and beyond
Jacobs, A. L., & Schär, P. (2012) · Chromosoma · doi:10.1007/s00412-011-0347-4 · Cited by 407 · see citing works
Yan, S., Sorrell, M., & Berman, Z. (2014) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-014-1666-4 · Cited by 247 · see citing works
The mismatch repair‐mediated cell cycle checkpoint response to fluorodeoxyuridine
Liu, A., Yoshioka, K., Salerno, V., & Hsieh, P. (2008) · Journal of Cellular Biochemistry · doi:10.1002/jcb.21824 · Cited by 50 · see citing works
Gmeiner, W. H., Dominijanni, A., Haber, A. O., Ghiraldeli, L. P., Caudell, D. L., D’Agostino, R., Pasche, B. C., Smith, T. L., Deng, Z., Kiren, S., et al. (2021) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-20-0516 · Cited by 21 · see citing works
- Authors
- An, Q., Robins, P., Lindahl, T., & Barnes, D. E.
- Affiliations
- Cancer Research UK (GB)
- Venue
- Cancer Research
- Published
- 2007-02-01
- Volume
- 67
- Issue
- 3
- Pages
- 940-945
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2096588719
- Cited by
- 134
- References
- 35
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 1 · 2023: 5 · 2022: 8 · 2021: 9 · 2020: 3 · 2019: 8 · 2018: 4 · 2017: 4 · 2016: 9 · 2015: 8 · 2014: 5 · 2013: 6 · 2012: 11
- FWCI
- 3.85
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- 5-fluorouracil, uracil-DNA glycosylase, DNA repair, drug cytotoxicity, thymidylate synthase inhibition, DNA replication, acquired drug resistance, predictive biomarkers
- MeSH terms
- Animals, Antimetabolites, Antineoplastic, Cell Line, DNA, DNA Damage, DNA Repair, Fibroblasts, Fluorouracil, Humans, RNA, Small Interfering, Mice, Uracil-DNA Glycosidase
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
