DOI: 10.1126/science.1697983. 5-Methylcytosine as an Endogenous Mutagen in the Human LDL Receptor and p53 Genes

5-Methylcytosine as an Endogenous Mutagen in the Human LDL Receptor and p53 Genes

10.1126/science.1697983

Crossref journal-article

American Association for the Advancement of Science (AAAS)

Science (221)

Abstract

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.

Bibliography

Rideout, W. M., Coetzee, G. A., Olumi, A. F., & Jones, P. A. (1990). 5-Methylcytosine as an Endogenous Mutagen in the Human LDL Receptor and p53 Genes. Science, 249(4974), 1288â1290.

Authors 4

William M. Rideout (first)
Gerhard A. Coetzee (additional)
Aria F. Olumi (additional)
Peter A. Jones (additional)

References 26 Referenced 457

BARKER, D, RESTRICTION SITES CONTAINING CPG SHOW A HIGHER FREQUENCY OF POLYMORPHISM IN HUMAN DNA, CELL 36: 131 (1984). (10.1016/0092-8674(84)90081-3) / CELL (1984)
BIRD, A.P., USE OF RESTRICTION ENZYMES TO STUDY EUKARYOTIC DNA METHYLATION .2. SYMMETRY OF METHYLATED SITES SUPPORTS SEMI-CONSERVATIVE COPYING OF METHYLATION PATTERN, JOURNAL OF MOLECULAR BIOLOGY 118: 49 (1978). (10.1016/0022-2836(78)90243-7) / JOURNAL OF MOLECULAR BIOLOGY (1978)
BIRD, A.P., CPG ISLANDS AS GENE MARKERS IN THE VERTEBRATE NUCLEUS, TRENDS IN GENETICS 3: 342 (1987). (10.1016/0168-9525(87)90294-0) / TRENDS IN GENETICS (1987)
10.1073/pnas.81.7.1991
COOPER, D.N., THE CPG DINUCLEOTIDE AND HUMAN GENETIC-DISEASE, HUMAN GENETICS 78: 151 (1988). (10.1007/BF00278187) / HUMAN GENETICS (1988)
COULONDRE, C, MOLECULAR-BASIS OF BASE SUBSTITUTION HOTSPOTS IN ESCHERICHIA-COLI, NATURE 274: 775 (1978). (10.1038/274775a0) / NATURE (1978)
DOERFLER, W, DNA METHYLATION AND GENE ACTIVITY, ANNUAL REVIEW OF BIOCHEMISTRY 52: 93 (1983). (10.1146/annurev.bi.52.070183.000521) / ANNUAL REVIEW OF BIOCHEMISTRY (1983)
EHRLICH, M, DNA CYTOSINE METHYLATION AND HEAT-INDUCED DEAMINATION, BIOSCIENCE REPORTS 6: 387 (1986). (10.1007/BF01116426) / BIOSCIENCE REPORTS (1986)
EHRLICH, M, AMOUNT AND DISTRIBUTION OF 5-METHYLCYTOSINE IN HUMAN DNA FROM DIFFERENT TYPES OF TISSUES OR CELLS, NUCLEIC ACIDS RESEARCH 10: 2709 (1982). (10.1093/nar/10.8.2709) / NUCLEIC ACIDS RESEARCH (1982)
10.1126/science.2294591
GRIPPO, P, METHYLATION OF DNA IN DEVELOPING SEA URCHIN EMBRYOS, JOURNAL OF MOLECULAR BIOLOGY 36: 195 (1968). (10.1016/0022-2836(68)90375-6) / JOURNAL OF MOLECULAR BIOLOGY (1968)
HO, Y.K., REGULATION OF LOW-DENSITY LIPOPROTEIN RECEPTOR ACTIVITY IN FRESHLY ISOLATED HUMAN LYMPHOCYTES, JOURNAL OF CLINICAL INVESTIGATION 58: 1465 (1976). (10.1172/JCI108603) / JOURNAL OF CLINICAL INVESTIGATION (1976)
JONES, P.A., ADVANCES IN CANCER RESEARCH 54: 1 (1990). (10.1016/S0065-230X(08)60806-4) / ADVANCES IN CANCER RESEARCH (1990)
KEITH, D.H., ACTIVE X-CHROMOSOME DNA IS UNMETHYLATED AT 8 CCGG SITES CLUSTERED IN A GUANINE-PLUS-CYTOSINE-RICH ISLAND AT THE 5' END OF THE GENE FOR PHOSPHOGLYCERATE KINASE, MOLECULAR AND CELLULAR BIOLOGY 6: 4122 (1986). / MOLECULAR AND CELLULAR BIOLOGY (1986)
LEITERSDORF, E, 2 COMMON LOW-DENSITY LIPOPROTEIN RECEPTOR GENE-MUTATIONS CAUSE FAMILIAL HYPERCHOLESTEROLEMIA IN AFRIKANERS, JOURNAL OF CLINICAL INVESTIGATION 84: 954 (1989). (10.1172/JCI114258) / JOURNAL OF CLINICAL INVESTIGATION (1989)
LINDAHL, T, PROG NUCLEIC ACID RE 22: 135 (1979). (10.1016/S0079-6603(08)60800-4) / PROG NUCLEIC ACID RE (1979)
LUBBERT, M, EXPRESSION, METHYLATION AND CHROMATIN STRUCTURE OF THE P53-GENE IN UNTRANSFORMED AND HUMAN T-CELL LEUKEMIA-VIRUS TYPE-I-TRANSFORMED HUMAN LYMPHOCYTE-T, ONCOGENE 4: 643 (1989). / ONCOGENE (1989)
10.1126/science.2814500
10.1038/342705a0
10.1126/science.2814502
RIDEOUT W unpublished data.
SELKER, E.U., SIGNAL FOR DNA METHYLATION ASSOCIATED WITH TANDEM DUPLICATION IN NEUROSPORA-CRASSA, MOLECULAR AND CELLULAR BIOLOGY 7: 1032 (1987). / MOLECULAR AND CELLULAR BIOLOGY (1987)
SELKER, E.U., DNA METHYLATION AT ASYMMETRIC SITES IS ASSOCIATED WITH NUMEROUS TRANSITION MUTATIONS, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 82: 8114 (1985). / PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (1985)
TSAI, Y.C., ALLELIC LOSSES OF CHROMOSOME-9, CHROMOSOME-11, AND CHROMOSOME-17 IN HUMAN BLADDER-CANCER, CANCER RESEARCH 50: 44 (1990). / CANCER RESEARCH (1990)
WOLF, S.F., METHYLATION OF THE HYPOXANTHINE PHOSPHORIBOSYLTRANSFERASE LOCUS ON THE HUMAN X-CHROMOSOME - IMPLICATIONS FOR X-CHROMOSOME INACTIVATION, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES 81: 2806 (1984). / PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES (1984)
10.1056/NEJM198912213212501

Dates

Type	When
Created	18 years, 10 months ago (Oct. 5, 2006, 6:10 p.m.)
Deposited	1 year, 7 months ago (Jan. 11, 2024, 10:50 a.m.)
Indexed	4 weeks, 2 days ago (Aug. 2, 2025, 1:02 a.m.)
Issued	34 years, 11 months ago (Sept. 14, 1990)
Published	34 years, 11 months ago (Sept. 14, 1990)
Published Print	34 years, 11 months ago (Sept. 14, 1990)

Funders 0

None

BibTeX

@article{Rideout_1990, title={5-Methylcytosine as an Endogenous Mutagen in the Human LDL Receptor and p53 Genes}, volume={249}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.1697983}, DOI={10.1126/science.1697983}, number={4974}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Rideout, William M. and Coetzee, Gerhard A. and Olumi, Aria F. and Jones, Peter A.}, year={1990}, month=sep, pages={1288–1290} }

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