5-Methylcytosine as an endogenous mutagen in the human LDL receptor and p53 genes.
Direct genomic sequencing revealed that cytosine residues known to have undergone a germ-line mutation in the low density lipoprotein receptor gene or somatic mutations in the p53 tumor suppressor gene were methylated in all normal human tissues analyzed. Thus, these mutations should be scored as transitions from 5-methylcytosine to thymine rather than from cytosine to thymine. Methylated cytosines occur exclusively at CpG dinucleotides, which, although markedly underrepresented in human DNA, are sites for more than 30 percent of all known disease-related point mutations. Thus, 5-methylcytosine functions as an endogenous mutagen and carcinogen in humans, in that methylation seems to increase the potential for mutation at cytosine residues at least by a factor of 10.
Rideout
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Urological Cancer Research Laboratory, Kenneth Norris Jr. Comprehensive Cancer Center, University of Southern California, Los Angeles 90033.
Coetzee
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Olumi
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Jones
P A
PA
D044503:5-Methylcytosine; D001483:Base Sequence; D003596:Cytosine / Q000031:analogs & derivatives* / Q000502:physiology; D019003:Deoxyribonuclease HpaII; D015252:Deoxyribonucleases, Type II Site-Specific; D015226:Dinucleoside Phosphates / Q000235:genetics; D006151:Guanosine; D006801:Humans; D007962:Leukocytes; D008297:Male; D008745:Methylation; D008969:Molecular Sequence Data; D009154:Mutation; D015513:Oncogene Proteins / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011973:Receptors, LDL / Q000235:genetics*; D013094:Spermatozoa; D016159:Tumor Suppressor Protein p53
D015226:Dinucleoside Phosphates; D015513:Oncogene Proteins; D010750:Phosphoproteins; D011973:Receptors, LDL; D016159:Tumor Suppressor Protein p53; D006151:Guanosine; D044503:5-Methylcytosine; D003596:Cytosine; D019003:Deoxyribonuclease HpaII; D015252:Deoxyribonucleases, Type II Site-Specific