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Mutagenesis at Methylated CpG Sequences

  • Chapter
DNA Methylation: Basic Mechanisms

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 301))

Abstract

5-Methylcytosine in DNA is genetically unstable. Methylated CpG (mCpG) sequences frequently undergo mutation resulting in a general depletion of this dinucleotide sequence in mammalian genomes. In human genetic disease- and cancerrelevant genes, mCpG sequences are mutational hotspots. It is an almost universally accepted dogma that these mutations are caused by random deamination of 5-methylcytosines. However, it is plausible that mCpG transitions are not caused simply by spontaneous deamination of 5-methylcytosine in double-stranded DNA but by other processes including, for example, mCpG-specific base modification by endogenous or exogenous mutagens or, alternatively, by secondary factors operating at mCpG sequences and promoting deamination. We also discuss that mCpG sequences are favored targets for specific exogenous mutagens and carcinogens. When adjacent to another pyrimidine, 5-methylcytosine preferentially undergoes sunlight-induced pyrimidine dimer formation. Certain polycyclic aromatic hydrocarbons form guanine adducts and induce G to T transversion mutations with high selectivity at mCpG sequences.

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References

  • Abu M, Waters TR (2003) The main role of human thymine-DNA glycosylase is removal of thymine produced by deamination of 5-methylcytosine and not removal of ethenocytosine. J Biol Chem 278:8739–8744

    Article  CAS  PubMed  Google Scholar 

  • Aguilar F, Hussain SP, Cerutti P (1993) Aflatoxin B1 induces the transversion of G→T in codon 249 of the p53 tumor suppressor gene in human hepatocytes. Proc Natl Acad Sci USA 90:8586–8590

    CAS  PubMed  Google Scholar 

  • Ambs S, Bennett WP, Merriam WG, Ogunfusika MO, Oser SM, Harrington AM, Shields PG, Felley-Bosco E, Hussain SP, Harris CC (1999b) Relationship between p53 mutations and inducible nitric oxide synthase expression in human colorectal cancer. J Natl Cancer Inst 91:86–88

    CAS  PubMed  Google Scholar 

  • Barbacid M (1987) ras genes. Annu Rev Biochem 56:779–827

    Article  CAS  PubMed  Google Scholar 

  • Bentivegna SS, Bresnick E (1994) Inhibition of human O6-methylguanine-DNA methyltransferase by 5-methylcytosine. Cancer Res 54:327–329

    CAS  PubMed  Google Scholar 

  • Bill CA, Duran WA, Miselis NR, Nickoloff JA (1998) Efficient repair of all types of singlebase mismatches in recombination intermediates in Chinese hamster ovary cells: competition between long-patch and G-T glycosylase-mediated repair of G-T mismatches. Genetics 149:1935–1943

    CAS  PubMed  Google Scholar 

  • Biramijamal F, Allameh A, Mirbod P, Groene HJ, Koomagi R, Hollstein M (2001) Unusual profile and high prevalence of p53 mutations in esophageal squamous cell carcinomas from northern Iran. Cancer Res 61:3119–3123

    CAS  PubMed  Google Scholar 

  • Bodell WJ, Gaikwad NW, Miller D, Berger MS (2003) Formation of DNA adducts and induction of lacI mutations in Big Blue Rat-2 cells treated with temozolomide: implications for the treatment of low-grade adult and pediatric brain tumors. Cancer Epidemiol Biomarkers Prev 12:545–551

    CAS  PubMed  Google Scholar 

  • Boorstein RJ, Cummings A Jr, Marenstein DR, Chan MK, Ma Y, Neubert TA, Brown SM, Teebor GW (2001) Definitive identification of mammalian 5-hydroxymethyluracil DNA N-glycosylase activity as SMUG1. J Biol Chem 276:41991–41997

    Article  CAS  PubMed  Google Scholar 

  • Brash DE, Rudolph JA, Simon JA, Lin A, McKenna GJ, Baden HP, Halperin AJ, Pontén J (1991) A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma. Proc Natl Acad Sci USA 88:10124–10128

    CAS  PubMed  Google Scholar 

  • Burdzy A, Noyes KT, Valinluck V, Sowers LC (2002) Synthesis of stable-isotope enriched 5-methylpyrimidines and their use as probes of base reactivity in DNA. Nucleic Acids Res 30:4068–4074

    Article  CAS  PubMed  Google Scholar 

  • Chen JX, Zheng Y, West M, Tang M-s (1998) Carcinogens preferentially bind at methylated CpG in the p53 mutational hotspots. Cancer Res 58:2070–2075

    CAS  PubMed  Google Scholar 

  • Chen R-H, Maher VM, McCormick JJ (1990) Effect of excision repair by diploid human fibroblasts on the kinds and locations of mutations induced by (±)-7b,8a-dihydroxy-9a,10a-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene in the coding region of the HPRT gene. Proc Natl Acad Sci USA 87:8680–8684

    CAS  PubMed  Google Scholar 

  • Coulondre C, Miller JH, Farabaugh PJ, Gilbert W (1978) Molecular basis of base substitution hotspots in Escherichia coli. Nature 274:775–780

    Article  CAS  PubMed  Google Scholar 

  • Denissenko MF, Pao A, Tang M-s, Pfeifer GP (1996) Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53. Science 274:430–432

    Article  CAS  PubMed  Google Scholar 

  • Denissenko MF, Chen JX, Tang M-s, Pfeifer GP (1997) Cytosine methylation determines hot spots of DNA damage in the human P53 gene. Proc Natl Acad Sci USA 94:3893–3898

    Article  CAS  PubMed  Google Scholar 

  • Denissenko MF, Pao A, Pfeifer GP, Tang M-s (1998a) Slow repair of bulky DNA adducts along the nontranscribed strand of the human p53 gene may explain the strand bias of transversion mutations in cancers. Oncogene 16:1241–1247

    Article  CAS  PubMed  Google Scholar 

  • Di Noia J, Neuberger MS (2002) Altering the pathway of immunoglobulin hypermutation by inhibiting uracil-DNA glycosylase. Nature 419:43–48

    PubMed  Google Scholar 

  • Drouin R, Therrien J-P (1997) UVB-induced cyclobutane pyrimidine dimer frequency correlates with skin cancer mutational hotspots in p53. Photochem Photobiol 66:719–726

    CAS  PubMed  Google Scholar 

  • Dumaz N, Drougard C, Sarasin A, Daya-Grosjean L (1993) Specific UV-induced mutation spectrum in the p53 gene of skin tumors from DNA-repair-deficient xeroderma pigmentosum patients. Proc Natl Acad Sci USA 90:10529–10533

    CAS  PubMed  Google Scholar 

  • Duncan BK, Miller JH (1980) Mutagenic deamination of cytosine residues in DNA. Nature 287:560–561

    Article  CAS  PubMed  Google Scholar 

  • Ehrlich M, Norris KF, Wang RY, Kuo KC, Gehrke CW (1986) DNA cytosine methylation and heat-induced deamination. Biosci Rep 6:387–393

    Article  CAS  PubMed  Google Scholar 

  • Ehrlich M, Zhang X-Y, Inamdar NM (1990) Spontaneous deamination of cytosine and 5-methylcytosine residues in DNA and replacement of 5-methylcytosine residues with cytosine residues. Mutat Res 238:277–286

    CAS  PubMed  Google Scholar 

  • El-Deiry WS, Nelkin BD, Celano P, Yen RW, Falco JP, Hamilton SR, Baylin SB (1991) High expression of the DNA methyltransferase gene characterizes human neoplastic cells and progression stages of colon cancer. Proc Natl Acad Sci USA 88:3470–3474

    CAS  PubMed  Google Scholar 

  • Felley-Bosco E, Mirkovitch J, Ambs S, Mace K, Pfeifer A, Keefer LK, Harris CC (1995) Nitric oxide and ethylnitrosourea: relativemutagenicity in the p53 tumor suppressor and hypoxanthine-phosphoribosyltransferase genes. Carcinogenesis 16:2069–2074

    CAS  PubMed  Google Scholar 

  • Fischhaber PL, Gerlach VL, Feaver WJ, Hatahet Z, Wallace SS, Friedberg EC (2002) Human DNA polymerase kappa bypasses and extends beyond thymine glycols during translesion synthesis in vitro, preferentially incorporating correct nucleotides. J Biol Chem 277:37604–37611

    Article  CAS  PubMed  Google Scholar 

  • Frederico LA, Kunkel TA, Shaw BR (1990) A sensitive genetic assay for the detection of cytosine deamination: determination of rate constants and the activation energy. Biochemistry 29:2532–2537

    Article  CAS  PubMed  Google Scholar 

  • Frederico LA, Kunkel TA, Shaw BR (1993) Cytosine deamination in mismatched base pairs. Biochemistry 32:6523–6530

    Article  CAS  PubMed  Google Scholar 

  • Geacintov NE, Shabaz M, Ibanez V, Moussaoui K, harvey RG (1988) Base-sequence dependence of noncovalent complex formation and reactivity of benzo[a]pyrene diol epoxide with polynucleotides. Biochemistry 27:8380–8387

    Article  CAS  PubMed  Google Scholar 

  • Gonzalgo ML, Jones PA (1997) Mutagenic and epigenetic effects of DNA methylation. Mutat Res 386:107–118

    CAS  PubMed  Google Scholar 

  • Greenblatt MS, Bennett WP, Hollstein M, Harris CC (1994) Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 54:4855–4878

    CAS  PubMed  Google Scholar 

  • Hainaut P, Olivier M, Pfeifer GP (2001) TP53 mutation spectrum in lung cancers and mutagenic signature of components of tobacco smoke: lessons from the IARC TP53 mutation database. Mutagenesis 16:551–553; author reply 555–556

    Article  CAS  PubMed  Google Scholar 

  • Halliwell B (2002) Effect of diet on cancer development: is oxidative DNA damage a biomarker? Free Radic Biol Med 32:968–974

    Article  CAS  PubMed  Google Scholar 

  • Hang B, Medina M, Fraenkel-Conrat H, Singer B (1998) A 55-kDa protein isolated from human cells shows DNA glycosylase activity toward 3,N4-ethenocytosine and the G/T mismatch. Proc Natl Acad Sci USA 95:13561–13566

    Article  CAS  PubMed  Google Scholar 

  • Hardeland U, Bentele M, Jiricny J, Schar P (2003) The versatile thymine DNA glycosylase: a comparative characterization of the human, Drosophila and fission yeast orthologs. Nucleic Acids Res 31:2261–2271

    Article  CAS  PubMed  Google Scholar 

  • Harris RS, Petersen-Mahrt SK, Neuberger MS (2002) RNA editing enzyme APOBEC1 and some of its homologs can act as DNA mutators. Mol Cell 10:1247–1253

    Article  CAS  PubMed  Google Scholar 

  • Haushalter KA, Todd Stukenberg MW, Kirschner MW, Verdine GL (1999) Identification of a new uracil-DNA glycosylase family by expression cloning using synthetic inhibitors. Curr Biol 9:174–185

    Article  CAS  PubMed  Google Scholar 

  • Hecht SS (1999) Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst 91:1194–1210

    Article  CAS  PubMed  Google Scholar 

  • Hendrich B, Hardeland U, Ng H-H, Jiricny J, Bird A (1999) The thymine glycosylase MBD4 can bind to the product of deamination at methylated CpG sites. Nature 401:301–304

    CAS  PubMed  Google Scholar 

  • Hennecke F, Kolmar H, Brundl K, Fritz HJ (1991) The vsr gene product of E. coli K-12 is a strand-and sequence-specific DNA mismatch endonuclease. Nature 353:776–778

    Article  CAS  PubMed  Google Scholar 

  • Hernandez-Boussard TM, Hainaut P (1998) A specific spectrum of p53 mutations in lung cancer from smokers: review of mutations compiled in the IARC p53 database. Environ Health Perspect 106:385–391

    CAS  PubMed  Google Scholar 

  • Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991) p53 mutations in human cancers. Science 253:49–53

    CAS  PubMed  Google Scholar 

  • Holmquist GP (1998) Endogenous lesions, S-phase-independent spontaneous mutations, and evolutionary strategies for base excision repair. Mutat Res 400:59–68

    CAS  PubMed  Google Scholar 

  • Hussain SP, Harris CC (1998) Molecular epidemiology of human cancer: contribution of mutation spectra studies of tumor suppressor genes. Cancer Res 58:4023–4037

    CAS  PubMed  Google Scholar 

  • Hussain SP, Amstad P, Raja K, Ambs S, Nagashima M, Bennett WP, Shields PG, Ham AJ, Swenberg JA, Marrogi AJ, Harris CC (2000) Increased p53 mutation load in noncancerous colon tissue from ulcerative colitis: a cancer-prone chronic inflammatory disease. Cancer Res 60:3333–3337

    CAS  PubMed  Google Scholar 

  • Jackson AL, Loeb LA (2001) The contribution of endogenous sources of DNA damage to the multiple mutations in cancer. Mutat Res 477:7–21

    CAS  PubMed  Google Scholar 

  • Johnson RE, Yu SL, Prakash S, Prakash L (2003) Yeast DNA polymerase zeta (zeta) is essential for error-free replication past thymine glycol. Genes Dev 17:77–87

    Article  CAS  PubMed  Google Scholar 

  • Jonason AS, Kunala S, Price GJ, Restifo RJ, Spinelli HM, Persing JA, Leffell DJ, Tarone RE, Brash DE (1996) Frequent clones of p53-mutated keratinocytes in normal human skin. Proc Natl Acad Sci USA 93:14025–14029

    Article  CAS  PubMed  Google Scholar 

  • Jones PA (1996) DNA methylation errors and cancer. Cancer Res 56:2463–2467

    CAS  PubMed  Google Scholar 

  • Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428

    Article  CAS  PubMed  Google Scholar 

  • Jones PA, Rideout WM, Shen J-C, Spruck CH, Tsai YC (1992) Methylation, mutation and cancer. BioEssays 14:33–36

    CAS  PubMed  Google Scholar 

  • Kamiya H, Murata-Kamiya N, Karino N, Ueno Y, Matsuda A, Kasai H (2002a) Induction of T→G and T→A transversions by 5-formyluracil in mammalian cells. Mutat Res 513:213–222

    CAS  PubMed  Google Scholar 

  • Kamiya H, Tsuchiya H, Karino N, Ueno Y, Matsuda A, Harashima H (2002b) Mutagenicity of 5-formylcytosine, an oxidation product of 5-methylcytosine, in DNA in mammalian cells. J Biochem (Tokyo) 132:551–555

    CAS  PubMed  Google Scholar 

  • Kasai H, Iwamoto-Tanaka N, Fukada S (1998) DNA modifications by the mutagen glyoxal: adduction to G and C, deamination of C and GC and GA cross-linking. Carcinogenesis 19:1459–1465

    Article  CAS  PubMed  Google Scholar 

  • Kavli B, Sundheim O, Akbari M, Otterlei M, Nilsen H, Skorpen F, Aas PA, Hagen L, Krokan HE, Slupphaug G (2002) hUNG2 is the major repair enzyme for removal of uracil from U:A matches, U:G mismatches, and U in single-stranded DNA, with hSMUG1 as a broad specificity backup. J Biol Chem 277:39926–39936

    Article  CAS  PubMed  Google Scholar 

  • Klimasauskas S, Kumar S, Roberts RJ, Cheng X (1994) HhaI methyltransferase flips its target base out of the DNA helix. Cell 76:357–369

    Article  CAS  PubMed  Google Scholar 

  • Knoll A, Jacobson DP, Kretz PL, Lundberg KS, Short JM, Sommer SS (1994) Spontaneous mutations in lacI-containing lambda lysogens derived from transgenic mice: the observed patterns differ in liver and spleen. Mutat Res 311:57–67

    CAS  PubMed  Google Scholar 

  • Krawczak M, Ball EV, Cooper DN (1998) Neighboring-nucleotide effects on the rates of germ-line single-base-pair substitution in human genes. Am J Hum Genet 63:474–488

    Article  CAS  PubMed  Google Scholar 

  • Krokan HE, Drablos F, Slupphaug G (2002) Uracil in DNA-occurrence, consequences and repair. Oncogene 21:8935–8948

    Article  CAS  PubMed  Google Scholar 

  • Kusumoto R, Masutani C, Iwai S, Hanaoka F (2002) Translesion synthesis by human DNA polymerase eta across thymine glycol lesions. Biochemistry 41:6090–6099

    Article  CAS  PubMed  Google Scholar 

  • Laird PW, Jaenisch R (1996) The role of DNA methylation in cancer genetics and epigenetics. Annu Rev Genet 30:441–464

    Article  CAS  PubMed  Google Scholar 

  • Larijani M, Frieder D, Sonbuchner TM, Bransteitter R, Goodman MF, Bouhassira EE, Scharff MD, Martin A (2005) Methylation protects cytidines from AID-mediated deamination. Mol Immunol 42:599–604

    Article  CAS  PubMed  Google Scholar 

  • Lee DH, Pfeifer GP (2003) Deamination of 5-methylcytosines within cyclobutane pyrimidine dimers is an important component of UVB mutagenesis. J Biol Chem 278:10314–10321

    CAS  PubMed  Google Scholar 

  • Lee DH, O’Connor TR, Pfeifer GP (2002) Oxidative DNA damage induced by copper and hydrogen peroxide promotes CG→TT tandem mutations at methylated CpG dinucleotides in nucleotide excision repair-deficient cells. Nucleic Acids Res 30:3566–3573

    CAS  PubMed  Google Scholar 

  • Li F, Segal A, Solomon JJ (1992) In vitro reaction of ethylene oxide with DNA and characterization of DNA adducts. Chem Biol Interact 83:35–54

    CAS  PubMed  Google Scholar 

  • Lieb M (1991) Spontaneous mutation at a 5-methylcytosine hotspot is prevented by very short patch (VSP) mismatch repair. Genetics 128:23–27

    CAS  PubMed  Google Scholar 

  • Lindahl T (1993) Instability and decay of the primary structure of DNA. Nature 362:709–715

    Article  CAS  PubMed  Google Scholar 

  • Malia SA, Basu AK (1994) Reductive metabolism of 1-nitropyrene accompanies deamination of cytosine. Chem Res Toxicol 7:823–828

    Article  CAS  PubMed  Google Scholar 

  • Marnett LJ, Burcham PC (1993) Endogenous DNA adducts: potential and paradox. Chem Res Toxicol 6:771–785

    CAS  PubMed  Google Scholar 

  • Millar CB, Guy J, Sansom OJ, Selfridge J, MacDougall E, Hendrich B, Keightley PD, Bishop SM, Clarke AR, Bird A (2002) Enhanced CpG mutability and tumorigenesis in MBD4-deficient mice. Science 297:403–405

    Article  CAS  PubMed  Google Scholar 

  • Morgan HD, Dean W, Coker HA, Reik W, Petersen-Mahrt SK (2004) Activation-induced cytidine deaminase deaminates 5-methylcytosine in DNA and is expressed in pluripotent tissues: implications for epigenetic reprogramming. J Biol Chem 279:52353–52360

    CAS  PubMed  Google Scholar 

  • Mortimer P (1991) Squamous cell and basal cell skin carcinoma and rarer histologic types of skin cancer. Curr Opin Oncol 3:349–354

    CAS  PubMed  Google Scholar 

  • Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T (2000) Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102:553–563

    Article  CAS  PubMed  Google Scholar 

  • Neddermann P, Gallinari P, Lettieri T, Schmid D, Truong O, Hsuan JJ, Wiebauer K, Jiricny J (1996) Cloning and expression of humanG/T mismatch-specific thymine-DNA glycosylase. J Biol Chem 271:12767–12774

    CAS  PubMed  Google Scholar 

  • Nilsen H, Rosewell I, Robins P, Skjelbred CF, Andersen S, Slupphaug G, Daly G, Krokan HE, Lindahl T, Barnes DE (2000) Uracil-DNA glycosylase (UNG)-deficient mice reveal a primary role of the enzyme during DNA replication. Mol Cell 5:1059–1065

    Article  CAS  PubMed  Google Scholar 

  • Nilsen H, Haushalter KA, Robins P, Barnes DE, Verdine GL, Lindahl T (2001) Excision of deaminated cytosine from the vertebrate genome: role of the SMUG1 uracil-DNA glycosylase. EMBO J 20:4278–4286

    Article  CAS  PubMed  Google Scholar 

  • O’Neill JP, Finette BA (1998) Transition mutations at CpG dinucleotides are the most frequent in vivo spontaneous single-base substitution mutation in the human HPRT gene. Environ Mol Mutagen 32:188–191

    CAS  PubMed  Google Scholar 

  • Olivier M, Eeles R, Hollstein M, Khan MA, Harris CC, Hainaut P (2002) The IARC TP53 database: new online mutation analysis and recommendations to users. Hum Mutat 19:607–614

    Article  CAS  PubMed  Google Scholar 

  • Olsen LC, Aasland R, Wittwer CU, Krokan HE, Helland DE (1989) Molecular cloning of human uracil-DNA glycosylase, a highly conserved DNA repair enzyme. EMBO J 8:3121–3125

    CAS  PubMed  Google Scholar 

  • Parker BS, Buley T, Evison BJ, Cutts SM, Neumann GM, Iskander MN, Phillips DR (2004) Amolecular understanding of mitoxantrone-DNA adduct formation: effect of cytosine methylation and flanking sequences. J Biol Chem 279:18814–18823

    CAS  PubMed  Google Scholar 

  • Petersen-Mahrt SK, Harris RS, Neuberger MS (2002) AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification. Nature 418:99–103

    Article  CAS  PubMed  Google Scholar 

  • Pfeifer GP (1997) Formation and processing of UV photoproducts: effects of DNA sequence and chromatin environment. Photochem Photobiol 65:270–283

    CAS  PubMed  Google Scholar 

  • Pfeifer GP (2000) p53 mutational spectra and the role of methylated CpG sequences. Mutat Res 450:155–166

    CAS  PubMed  Google Scholar 

  • Pfeifer GP, Drouin R, Riggs AD, Holmquist GP (1991) In vivo mapping of a DNA adduct at nucleotide resolution: detection of pyrimidine (6-4) pyrimidone photoproducts by ligation-mediated polymerase chain reaction. Proc Natl Acad Sci USA 88:1374–1378

    CAS  PubMed  Google Scholar 

  • Pfeifer GP, Denissenko MF, Olivier M, Tretyakova N, Hecht SS, Hainaut P (2002) Tobacco smoke carcinogens, DNA damage and p53 mutations insmoking-associated cancers. Oncogene 21:7435–7451

    Article  CAS  PubMed  Google Scholar 

  • Pham P, Bransteitter R, Petruska J, Goodman MF (2003) Processive AID-catalysed cytosine deamination on single-stranded DNA simulates somatic hypermutation. Nature 424:103–107

    Article  CAS  PubMed  Google Scholar 

  • Privat E, Sowers LC (1996) Photochemical deamination and demethylation of 5-methylcytosine. Chem Res Toxicol 9:745–750

    Article  CAS  PubMed  Google Scholar 

  • Puisieux A, Lim S, Groopman J, Ozturk M (1991) Selective targeting of p53 gene mutational hotspots in human cancers by etiologically defined carcinogens. Cancer Res 51:6185–6189

    CAS  PubMed  Google Scholar 

  • Ramiro AR, Stavropoulos P, Jankovic M, Nussenzweig MC (2003) Transcription enhances AID-mediated cytidine deamination by exposing single-stranded DNA on the nontemplate strand. Nat Immunol 4:452–456

    Article  CAS  PubMed  Google Scholar 

  • Rideout WM 3rd, Coetzee GA, Olumi AF, Jones PA (1990) 5-Methylcytosine as an endogenous mutagen in the human LDL receptor and p53 genes. Science 249:1288–1290

    CAS  PubMed  Google Scholar 

  • Riggs AD, Jones PA (1983) 5-Methylcytosine, gene regulation, and cancer. Adv Cancer Res 40:1–30

    CAS  PubMed  Google Scholar 

  • Ruggeri B, DiRado M, Zhang SY, Bauer B, Goodrow T, Klein-Szanto AJP (1993) Benzo[a]pyrene-inducedmurine skin tumors exhibit frequent and characteristic G to T mutations in the p53 gene. Proc Natl Acad Sci USA 90:1013–1017

    CAS  PubMed  Google Scholar 

  • Rusmintratip V, Sowers LC (2000) An unexpectedly high excision capacity for mispaired 5-hydroxymethyluracil in human cell extracts. Proc Natl Acad Sci U S A 97:14183–14187

    Article  CAS  PubMed  Google Scholar 

  • Ruzcicska BP, Lemaire DGE (1995) DNA photochemistry. In: Horspool WM, Song P-S (eds) CRC handbook of organic photochemistry and photobiology. CRC Press, Boca Raton, pp 1289–1317

    Google Scholar 

  • Saparbaev M, Laval J (1998) 3,N4-Ethenocytosine, a highly mutagenic adduct, is a primary substrate for Escherichia coli double-stranded uracil-DNA glycosylase and human mismatch-specific thymine-DNA glycosylase. Proc Natl Acad Sci USA 95:8508–8513

    Article  CAS  PubMed  Google Scholar 

  • Schmutte C, Jones PA (1998) Involvement of DNA methylation in human carcinogenesis. Biol Chem 379:377–388

    CAS  PubMed  Google Scholar 

  • Schmutte C, Rideout WM, Shen JC, Jones PA (1994)Mutagenicity of nitric oxide is not caused by deamination of cytosine or 5-methylcytosine in double-stranded DNA. Carcinogenesis 15:2899–2903

    CAS  PubMed  Google Scholar 

  • Schmutte C, Yang AS, Beart RW, Jones PA (1995) Base excisionrepair of U:G mismatches at a mutational hotspot in the p53 gene is more efficient than base excision repair of T:G mismatches in extracts of human colon tumors. Cancer Res 55:3742–3746

    CAS  PubMed  Google Scholar 

  • Schmutte C, Yang AS, Nguyen TT, Beart RW, Jones PA (1996) Mechanisms for the involvement of DNA methylation in colon carcinogenesis. Cancer Res 56:2375–2381

    CAS  PubMed  Google Scholar 

  • Schorderet DF, Gartler SM (1992) Analysis of CpG suppression in methylated and nonmethylated species. Proc Natl Acad Sci USA 89:957–961

    CAS  PubMed  Google Scholar 

  • Sepehr A, Taniere P, Martel-Planche G, Zia’ee AA, Rastgar-Jazii F, Yazdanbod M, Etemad-Moghadam G, Kamangar F, Saidi F, Hainaut P (2001) Distinct pattern of TP53 mutations in squamous cell carcinoma of the esophagus in Iran. Oncogene 20:7368–7374

    Article  CAS  PubMed  Google Scholar 

  • Shen JC, Rideout WM, Jones PA (1992) High frequency mutagenesis by a DNA methyltransferase. Cell 71:1073–1080

    Article  CAS  PubMed  Google Scholar 

  • Shen JC, Rideout WM 3rd, Jones PA (1994) The rate of hydrolytic deamination of 5-methylcytosine in double-stranded DNA. Nucleic Acids Res 22:972–976

    CAS  PubMed  Google Scholar 

  • Sohail A, Lieb M, Dar M, Bhagwat AS (1990) Agene required for very short patch repair in Escherichia coli is adjacent to the DNA cytosine methylase gene. J Bacteriol 172:4214–4221

    CAS  PubMed  Google Scholar 

  • Sohail A, Klapacz J, Samaranayake M, Ullah A, Bhagwat AS (2003) Human activationinduced cytidine deaminase causes transcription-dependent, strand-biased C to U deaminations. Nucleic Acids Res 31:2990–2994

    Article  CAS  PubMed  Google Scholar 

  • Sommer SS (1995) Recent human germ-line mutation: inferences from patients with hemophilia B. Trends Genet 11:141–147

    Article  CAS  PubMed  Google Scholar 

  • Souici AC, Mirkovitch J, Hausel P, Keefer LK, Felley-Bosco E (2000) Transition mutation in codon 248 of the p53 tumor suppressor gene induced by reactive oxygen species and a nitric oxide-releasing compound. Carcinogenesis 21:281–287

    Article  CAS  PubMed  Google Scholar 

  • Sowers LC, Shaw BR, Sedwick WD (1987) Base stacking and molecular polarizability: effect of a methyl group in the 5-position of pyrimidines. Biochem Biophys Res Commun 148:790–794

    Article  CAS  PubMed  Google Scholar 

  • Sved J, Bird A (1990) The expected equilibrium of the CpG dinucleotide in vertebrate genomes under a mutational model. Proc Natl Acad Sci USA 87:4692–4696

    CAS  PubMed  Google Scholar 

  • Tommasi S, Denissenko MF, Pfeifer GP (1997) Sunlight induces pyrimidine dimers preferentially at 5-methylcytosine bases. Cancer Res 57:4727–4730

    CAS  PubMed  Google Scholar 

  • Tornaletti S, Pfeifer GP (1994) Slow repair of pyrimidine dimers at p53 mutation hotspots in skin cancer. Science 263:1436–1438

    CAS  PubMed  Google Scholar 

  • Tornaletti S, Pfeifer GP (1995) Complete and tissue-independent methylation of CpG sites in the p53 gene: implications for mutations in human cancers. Oncogene 10:1493–1499

    CAS  PubMed  Google Scholar 

  • Tornaletti S, Rozek D, Pfeifer GP (1993) The distribution of UV photoproducts along the human p53 gene and its relation to mutations in skin cancer. Oncogene 8:2051–2057

    CAS  PubMed  Google Scholar 

  • Tretyakova N, Matter B, Jones R, Shallop A (2002) Formation of benzo[a]pyrene diol epoxide-DNA adducts at specific guanines within K-ras and p53 gene sequences: stable isotope-labeling mass spectrometry approach. Biochemistry 41:9535–9544

    Article  CAS  PubMed  Google Scholar 

  • Tu Y, Dammann R, Pfeifer GP (1998) Sequence and time-dependent deamination of cytosine bases in UVB-induced cyclobutane pyrimidine dimers in vivo. JMol Biol 284:297–311

    CAS  Google Scholar 

  • Wang RY, Gehrke CW, Ehrlich M (1980) Comparison of bisulfite modification of 5-methyldeoxycytidine and deoxycytidine residues. Nucleic Acids Res 8:4777–4790

    CAS  PubMed  Google Scholar 

  • Wang RY, Kuo KC, Gehrke CW, Huang LH, Ehrlich M (1982) Heat-and alkali-induced deamination of 5-methylcytosine and cytosine residues inDNA. Biochim Biophys Acta 697:371–377

    CAS  PubMed  Google Scholar 

  • Warren W, Biggs PJ, El-Baz M, Ghoneim MA, Stratton MR, Venitt S (1995) Mutations in the p53 gene in schistosomal bladder cancer: a study of 92 tumours from Egyptian patients and a comparison between mutational spectra from schistosomal and non-schistosomal urothelial tumours. Carcinogenesis 16:1181–1189

    CAS  PubMed  Google Scholar 

  • Waters TR, Swann PF (1998) Kinetics of the action of thymine DNA glycosylase. J Biol Chem 273:20007–20014

    Article  CAS  PubMed  Google Scholar 

  • Weisenberger DJ, 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. J Biol Chem 274:23948–23955

    Article  CAS  PubMed  Google Scholar 

  • Wink DA, Kasprzak KS, Maragos CM, Elespuru RK, Misra M, Dunams TM, Cebula TA, Koch WH, Andrews AW, Allen JS, Keefe LK (1991) DNA deaminating ability and genotoxicity of nitric oxide and its progenitors. Science 254:1001–1003

    CAS  PubMed  Google Scholar 

  • Wong E, Yang K, Kuraguchi M, Werling U, Avdievich E, Fan K, Fazzari M, Jin B, Brown AM, Lipkin M, Edelmann W (2002) Mbd4 inactivation increases C to T transition mutations and promotes gastrointestinal tumor formation. Proc Natl Acad Sci U S A 99:14937–14942

    CAS  PubMed  Google Scholar 

  • Wyatt GR, Cohen SS (1953) The bases of the nucleic acids of some bacterial and animal viruses: the occurrence of 5-hydroxymethylcytosine. Biochem J 55:774–782

    CAS  PubMed  Google Scholar 

  • Wyszynski M, Gabbara S, Bhagwat AS (1994) Cytosine deaminations catalyzed byDNA cytosine methyltransferases are unlikely to be the major cause of mutational hot spots at sites of cytosine methylation in Escherichia coli. Proc Natl Acad Sci USA 91:1574–1578

    CAS  PubMed  Google Scholar 

  • Yamanaka S, Balestra ME, Ferrell LD, Fan J, Arnold KS, Taylor S, Taylor JM, Innerarity TL (1995) Apolipoprotein B mRNA-editing protein induces hepatocellular carcinoma and dysplasia in transgenic animals. Proc Natl Acad Sci US A 92:8483–8487

    CAS  Google Scholar 

  • Yang AS, Shen JC, Zingg JM, Mi S, Jones PA (1995) HhaI and HpaII DNA methyltransferases bind DNA mismatches, methylate uracil and block DNA repair. Nucleic Acids Res 23:1380–1387

    CAS  PubMed  Google Scholar 

  • Yang AS, Gonzalgo ML, Zingg JM, Millar RP, Buckley JD, Jones PA (1996b) The rate of CpG mutation in Alu repetitive elements within the p53 tumor suppressor gene in the primate germline. J Mol Biol 258:240–250

    CAS  PubMed  Google Scholar 

  • Yebra MJ, Bhagwat AS (1995) A cytosine methyltransferase converts 5-methylcytosine in DNA to thymine. Biochemistry 34:14752–14757

    Article  CAS  PubMed  Google Scholar 

  • Yoon JH, Smith LE, Feng Z, Tang M, Lee CS, Pfeifer GP (2001) Methylated CpG dinucleotides are the preferential targets for G-to-T transversion mutations induced by benzo[a]pyrene diol epoxide in mammalian cells: similarities with the p53 mutation spectrum in smoking-associated lung cancers. Cancer Res 61:7110–7117

    CAS  PubMed  Google Scholar 

  • Yoon JH, Iwai S, O’Connor TR, Pfeifer GP (2003) Human thymine DNA glycosylase (TDG) and methyl-CpG-binding protein 4 (MBD4) excise thymine glycol (Tg) from a Tg:G mispair. Nucleic Acids Res 31:5399–5404

    CAS  PubMed  Google Scholar 

  • You YH, Li C, Pfeifer GP (1999) Involvement of 5-methylcytosine in sunlight-induced mutagenesis. J Mol Biol 293:493–503

    Article  CAS  PubMed  Google Scholar 

  • You YH, Lee DH, Yoon JH, Nakajima S, Yasui A, Pfeifer GP (2001) Cyclobutane pyrimidine dimers are responsible for the vast majority of mutations induced by UVB irradiation in mammalian cells. J Biol Chem 276:44688–44694

    CAS  PubMed  Google Scholar 

  • Zhang Q, Wang Y (2003) Independent generation of 5-(2′-deoxycytidinyl)methyl radical and the formation of a novel cross-link lesion between 5-methylcytosine and guanine. J Am Chem Soc 125:12795–12802

    CAS  PubMed  Google Scholar 

  • Zhang R, Takahashi S, Orita S, Yoshida A, Maruyama H, Shirai T, Ohta N (1998) p53 gene mutations in rectal cancer associated with schistosomiasis japonica in Chinese patients. Cancer Lett 131:215–221

    Article  CAS  PubMed  Google Scholar 

  • Ziegel R, Shallop A, Upadhyaya P, Jones R, Tretyakova N (2004) Endogenous 5-methylcytosine protects neighboring guanines fromN7 and O6-methylation and O6-pyridyloxobutylation by the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Biochemistry 43:540–549

    Article  CAS  PubMed  Google Scholar 

  • Ziegler A, Leffell DJ, Kunala S, Sharma HW, Gailani M, Simon JA, Halperin AJ, Baden HP, Shapiro PE, Bale AE, Brash DE (1993) Mutation hot spots due to sunlight in the p53 gene of nonmelanoma skin cancers. Proc Natl Acad Sci USA 90:4216–4220

    CAS  PubMed  Google Scholar 

  • Ziegler A, Jonason AS, Leffell DJ, Simon JA, Sharma HW, Kimmelman J, Remington L, Jacks T, Brash DE (1994) Sunburn and p53 in the onset of skin cancer. Nature 372:773–776

    Article  CAS  PubMed  Google Scholar 

  • Zuo S, Boorstein RJ, Teebor GW (1995) Oxidative damage to 5-methylcytosine in DNA. Nucleic Acids Res 25:3239–3243

    Google Scholar 

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  1. Division of Biology, Beckman Research Institute of the City of Hope, Duarte, CA, 91010, USA

    G. P. Pfeifer

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  1. Institut für Genetik, Universität zu Köln, Zülpicher Str. 47, 50674, Köln, Germany

    Walter Doerfler (Prof. Dr.) & Petra Böhm (Prof. Dr.) & 

  2. Institut für Klinische und Molekulare Virologie, Universität Erlangen, Schlossgarten 4, 91054, Erlangen, Germany

    Walter Doerfler (Prof. Dr.) (Prof. Dr.)

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Pfeifer, G.P. (2006). Mutagenesis at Methylated CpG Sequences. In: Doerfler, W., Böhm, P. (eds) DNA Methylation: Basic Mechanisms. Current Topics in Microbiology and Immunology, vol 301. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-31390-7_10

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