Mutagenic deamination of cytosine residues in DNA
Abstract
Spontaneous deamination converts cytosine to uracil, which is excised from DNA by the enzyme uracil-DNA glycosylase, leading to error-free repair. 5-Methylcytosine residues are deaminated to thymine, which cannot be excised and repaired by this system. As a result, 5-methylcytosine residues are hotspots for spontaneous transitions, as demonstrated in the lacI gene of Escherichia coli. We show here that in bacteria which lack uracil-DNA glycosylase (Ung-) and cannot excise uracil residues from DNA, the rate of spontaneous transition at cytosine residues is raised to the hotspot rate at 5-methylcytosine residues. These studies provide direct evidence that the deamination of cytosine is a significant source of spontaneous mutations.
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64% of recurrent de novo single nucleotide variants occurred at hypermutable CpG dinucleotides, a 2.0-fold enrichment over mutations observed only once (p = 3.3 × 10-68).
“Hypermutability underpins the observation that 64% of recurrent de novo SNVs occurred at hypermutable CpG dinucleotides24, a 2.0-fold enrichment over DNMs only observed once (p = 3.3 × 10-68, chi-square test).”
From Evidence for 28 genetic disorders discovered by combining healthcare and research data (2020) · cites this paper as [24]
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Molecular basis of base substitution hotspots in Escherichia coli
Coulondre, C., Miller, J. H., Farabaugh, P. J., & Gilbert, W. (1978) · Nature · doi:10.1038/274775a0 · Cited by 1,193 · see citing works
Self-citationHeat-induced deamination of cytosine residues in deoxyribonucleic acid
Lindahl, T. L., & Nyberg, B. (1974) · Biochemistry · doi:10.1021/bi00713a035 · Cited by 749 · see citing works
Lindahl, T. L. (1974) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.71.9.3649 · Cited by 605 · see citing works
Genetic studies of the lac repressor
Coulondre, C., & Miller, J. H. (1977) · Journal of Molecular Biology · doi:10.1016/0022-2836(77)90059-6 · Cited by 604 · see citing works
Self-citationDNA Glycosylases, Endonucleases for Apurinic/Apyrimidinic Sites, and Base Excision-Repair
Lindahl, T. L. (1979) · Progress in nucleic acid research and molecular biology · doi:10.1016/s0079-6603(08)60800-4 · Cited by 556 · see citing works
Genetic studies of the lac repressor
Miller, J. H., Ganem, D., Lu, P., & Schmitz, A. (1977) · Journal of Molecular Biology · doi:10.1016/s0022-2836(77)80034-x · Cited by 492 · see citing works
Self-citationTye, B., Chien, J. R., Lehman, I., Duncan, B. K., & Warner, H. R. (1978) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.75.1.233 · Cited by 153 · see citing works
Self-citationEscherichia coli K-12 mutants deficient in uracil-DNA glycosylase
Duncan, B. K., Rockstroh, P. A., & Warner, H. R. (1978) · Journal of Bacteriology · doi:10.1128/jb.134.3.1039-1045.1978 · Cited by 120 · see citing works
Self-citationURACIL-DNA GLYCOSYLASE MUTANTS ARE MUTATORS
Duncan, B. K., & Weiss, B. (1978) · DNA Repair Mechanisms · doi:10.1016/b978-0-12-322650-1.50034-5 · Cited by 17 · see citing works
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Epigenetic Reprogramming in Mammalian Development
Reik, W., Dean, W., & Walter, J. (2001) · Science · doi:10.1126/science.1063443 · Cited by 3,078 · see citing works
Clonal hematopoiesis in human aging and disease
Jaiswal, S., & Ebert, B. L. (2019) · Science · doi:10.1126/science.aan4673 · Cited by 1,156 · see citing works
“The most frequent class arises from the spontaneous deamination of 5methylcytosine to thymine and primarily occurs at CpG dinucleotides, which are often in the methylated state (6).”
Repair of Endogenous DNA Damage
LINDAHL, T., & BARNES, D. E. (2000) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2000.65.127 · Cited by 714 · see citing works
Evidence for 28 genetic disorders discovered by combining healthcare and research data
Kaplanis, J., Samocha, K. E., Wiel, L., Zhang, Z., Arvai, K. J., Eberhardt, R. Y., Gallone, G., Lelieveld, S. H., Martin, H. C., McRae, J. F., et al. (2020) · Nature · doi:10.1038/s41586-020-2832-5 · Cited by 615 · see citing works
DNA methylome profiling of human tissues identifies global and tissue-specific methylation patterns
Lokk, K., Modhukur, V., Rajashekar, B., Märtens, K., Mägi, R., Kolde, R., Koltšina, M., Nilsson, T. K., Vilo, J., Salumets, A., et al. (2014) · Genome Biology · doi:10.1186/gb-2014-15-4-r54 · Cited by 444 · see citing works
The genomics of oxidative DNA damage, repair, and resulting mutagenesis
Poetsch, A. R. (2020) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2019.12.013 · Cited by 420 · see citing works
Kennedy, S. R., Salk, J. J., Schmitt, M. W., & Loeb, L. A. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003794 · Cited by 363 · see citing works
Determinants of Mutation Rate Variation in the Human Germline
Ségurel, L., Wyman, M. J., & Przeworski, M. (2014) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-031714-125740 · Cited by 289 · see citing works
Coordination of DNA single strand break repair
Abbotts, R., & Wilson, D. M. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.11.039 · Cited by 240 · see citing works
Prebiotic cytosine synthesis: A critical analysis and implications for the origin of life
Shapiro, R. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.8.4396 · Cited by 172 · see citing works
Structures and functions of DNA glycosylases
Sakumi, K., & Sekiguchi, M. (1990) · Mutation Research/DNA Repair · doi:10.1016/0921-8777(90)90003-n · Cited by 106 · see citing works
Increased mutation and gene conversion within human segmental duplications
Vollger, M. R., Dishuck, P. C., Harvey, W. T., DeWitt, W. S., Guitart, X., Goldberg, M. E., Rozanski, A. N., Lucas, J., Asri, M., Human Pangenome Reference Consortium, et al. (2023) · Nature · doi:10.1038/s41586-023-05895-y · Cited by 104 · see citing works
Schuebel, K., Gitik, M., Domschke, K., & Goldman, D. (2016) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyw058 · Cited by 75 · see citing works
Senescence and epigenetic dysregulation in cancer
Neumeister, P., Albanese, C., Balent, B., Greally, J., & Pestell, R. G. (2002) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/s1357-2725(02)00079-1 · Cited by 56 · see citing works
Kaplanis, J., Samocha, K. E., Wiel, L., Zhang, Z., Arvai, K. J., Eberhardt, R. Y., Gallone, G., Lelieveld, S. H., Martin, H. C., McRae, J. F., et al. (2019) · doi:10.1101/797787 · Cited by 36 · see citing works
Magistroni, V., Mauri, M., D’Aliberti, D., Mezzatesta, C., Crespiatico, I., Nava, M., Fontana, D., Sharma, N., Parker, W., Schreiber, A., et al. (2019) · Haematologica · doi:10.3324/haematol.2017.179937 · Cited by 29 · see citing works
Cresti, J. R., & Simmons, L. A. (2026) · Molecular Microbiology · doi:10.1111/mmi.70047 · Cited by 2 · see citing works
- Authors
- Duncan, B. K., & Miller, J. H.
- Affiliations
- Johns Hopkins University (US)
- University of Geneva (CH)
- ORCID
- Miller, Jeffrey H.
- Venue
- Nature
- Published
- 1980-10
- Volume
- 287
- Issue
- 5782
- Pages
- 560-561
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2072063319
- Cited by
- 792
- References
- 9
- Citations by year
- 2026: 13 · 2025: 22 · 2024: 19 · 2023: 35 · 2022: 33 · 2021: 34 · 2020: 32 · 2019: 26 · 2018: 32 · 2017: 17 · 2016: 23 · 2015: 17 · 2014: 24 · 2013: 20 · 2012: 19
- FWCI
- 4.95
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (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 › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- cytosine deamination, spontaneous mutagenesis, 5-methylcytosine, uracil-DNA glycosylase, DNA repair, spontaneous transitions, lacI gene, Escherichia coli, mutational hotspots
- MeSH terms
- Cytidine Deaminase, Cytosine Nucleotides, DNA Repair, Escherichia coli, Methylation, Mutation, N-Glycosyl Hydrolases, Structure-Activity Relationship, DNA Glycosylases, Uracil-DNA Glycosidase
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