Gerd P Pfeifer, Beckman Research Institute of the City of Hope, Duarte, California, USA
Published online: January 2006
DOI: 10.1038/npg.els.0006159
The human genome contains about 50 million 5-methylcytosine bases, most of them occurring at the CpG dinucleotide sequence. Methylated CpG dinucleotides are the targets of several of the mutations, mostly transition mutations, found in human genetic diseases and cancer.
Keywords: DNA methylation; mutation; CpG sequence; 5-methylcytosine; DNA damage
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Figure 1. Two mechanisms that operate at methylated CpG sequences to produce mutational hot spots. Deamination of 5-methylcytosine can lead to C to T transition mutations after DNA replication. Preferential modification of guanines at methylated CpG sequences (indicated by x) can lead to G to T transversions after DNA replication. A double stranded methylated CPG sequence is shown.
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| References | |
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| Further Reading | |
| Bentivegna SS and Bresnick E (1994) Inhibition of human O6-methylguanine-DNA methyltransferase by 5-methylcytosine. Cancer Research 54: 327–329. | |
| Denissenko MF, Pao A, Tang M and Pfeifer GP (1996) Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in p53. Science 274: 430–432. | |
| Ehrlich M, Zhang XY and Inamdar NM (1990) Spontaneous deamination of cytosine and 5-methylcytosine residues in DNA and replacement of 5-methylcytosine residues with cytosine residues. Mutation Research 238: 277–286. | |
| Hussain SP and Harris CC (1998) Molecular epidemiology of human cancer: contribution of mutation spectra studies of tumor suppressor genes. Cancer Research 58: 4023–4037. | |
| Laird PW and Jaenisch R (1996) The role of DNA methylation in cancer genetics and epigenetics. Annual Reviews in Genetics 30: 441–464. | |
| Lindahl T (1993) Instability and decay of the primary structure of DNA. Nature 362: 709–715. | |
| Pfeifer GP, Tang M and Denissenko MF (2000) Mutation hotspots and DNA methylation. Current Topics in Microbiology and Immunology 249: 1–19. | |
| Rideout III WM, Coetzee GA, Olumi AF and Jones PA (1990) 5-Methylcytosine as an endogenous mutagen in the human LDL receptor and p53 genes. Science 249: 1288–1290. | |
| Schmutte C, Yang AS, Nguyen TDT, Beart RW and Jones PA (1996) Mechanisms for the involvement of DNA methylation in colon carcinogenesis. Cancer Research 56: 2375–2381. | |
| Weisenberger DJ and Romano LJ (1999) Cytosine methylation in a CpG sequence leads to enhanced reactivity with benzo[a]pyrene diol epoxide that correlates with a conformational change. Journal of Biological Chemistry 274: 23948–23955. | |
| Wyszynski M, Gabbara S and Bhagwat AS (1994) Cytosine deaminations catalyzed by DNA cytosine methyltransferases are unlikely to be the major cause of mutational hot spots at sites of cytosine methylation in Escherichia coli. Proceedings of the National Academy of Sciences of the United States of America 91: 1574–1578. | |
| Yang AS, Gonzalgo ML, Zingg JM, et al. (1996) The rate of CpG mutation in Alu repetitive elements within the p53 tumor suppressor gene in the primate germline. Journal of Molecular Biology 258: 240–250. | |
| You YH and Pfeifer GP (2001) Similarities in sunlight-induced mutational spectra of CpG-methylated transgenes and the p53 gene in skin cancer point to an important role of 5-methylcytosines in solar UV mutagenesis. Journal of Molecular Biology 305: 389–399. | |
| Zuo S, Boorstein RJ and Teebor GW (1995) Oxidative damage to 5-methylcytosine in DNA. Nucleic Acids Research 25: 3239–3243. | |
| Web Links | |
| ePath Human Gene Mutation Database http://archive.uwcm.ac.uk/uwcm/mg/hgmd0.html | |
| ePath International Agency for Research on Cancer http://www.iarc.fr/ | |
| ePath Tumor protein p53 (TP53); LocusID: 7157. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=7157 | |
| ePath Tumor protein p53 (TP53); MIM number: 191170. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?191170 | |
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