Effect of 5-methylcytosine as a neighboring base on methylation of DNA guanine by <i>N</i>-methyl-<i>N</i>-nitrosourea

Mathison, Brian H.; Said, Boctor; Shank, Ronald C.

doi:10.1093/carcin/14.2.323

Cited by 20 publications

(13 citation statements)

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“…Pixantrone joins an expanding catalogue of DNA-damaging agents that are susceptible to modulation by CpG methylation. Covalent modification of DNA by the chemical carcinogen N -methyl- N -nitrosourea (28) and UV-induced photoproducts (29,30) are both inhibited by proximal CpG methylation, yet other agents including the benzo[ a ]pyrene metabolite BPDE (24,31,32), aflatoxin B 1 -8,9-epoxide (33) and the therapeutic agents mitomycin C (9,21,34), esperamicins A1 and C (25) and formaldehyde-activated mitoxantrone (35,36) are all enhanced at methylated CpG dinucleotides. Given that each of these latter DNA-interactive agents (excluding the esperamicins A1 and C) alkylate DNA via the guanine residue of CpG doublets and are enhanced by methylation at the 5′ neighbouring cytosine, it would be appealing to establish if these compounds and formaldehyde-activated pixantrone share a common reaction mechanism in their alkylation of the methylated CpG motif.…”

Section: Discussionmentioning

confidence: 99%

CpG methylation potentiates pixantrone and doxorubicin-induced DNA damage and is a marker of drug sensitivity

Evison

Bilardi

Chiu

et al. 2009

Nucleic Acids Research

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DNA methylation is an epigenetic modification of the mammalian genome that occurs predominantly at cytosine residues of the CpG dinucleotide. Following formaldehyde activation, pixantrone alkylates DNA and particularly favours the CpG motif. Aberrations in CpG methylation patterns are a feature of most cancer types, a characteristic that may determine their susceptibility to specific drug treatments. Given their common target, DNA methylation may modulate the DNA damage induced by formaldehyde-activated pixantrone. In vitro transcription, mass spectrometry and oligonucleotide band shift assays were utilized to establish that pixantrone–DNA adduct formation was consistently enhanced 2–5-fold at discrete methylated CpG doublets. The methylation-mediated enhancement was exquisitely sensitive to the position of the methyl substituent since methylation at neighboring cytosine residues failed to confer an increase in pixantrone–DNA alkylation. Covalent modification of DNA by formaldehyde-activated doxorubicin, but not cisplatin, was augmented by neighbouring CpG methylation, indicating that modulation of binding by CpG methylation is not a general feature of all alkylators. HCT116 colon cancer cells vastly deficient in CpG methylation were 12- and 10-fold more resistant to pixantrone and doxorubicin relative to the wild-type line, suggesting that these drugs may selectively recognize the aberrant CpG methylation profiles characteristic of most tumour types.

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Section: Discussionmentioning

confidence: 99%

CpG methylation potentiates pixantrone and doxorubicin-induced DNA damage and is a marker of drug sensitivity

Evison

Bilardi

Chiu

et al. 2009

Nucleic Acids Research

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“…The effect of cytosine methylation of CpG sites on carcinogen-induced DNA modification has been analyzed in only a few other cases. N-methyl-N-nitrosoureadependent modification of the N7 position of guanine was shown to be inhibited when 5-mC was a 5Ј neighboring base (43). Methylation of cytosine also reduces formation of UV-induced (6-4) photoproducts (44,45).…”

Section: Discussionmentioning

confidence: 99%

Cytosine methylation determines hot spots of DNA damage in the human P 53 gene

Denissenko

Chen

Tang

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

320

232

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“…Methylation of CpG sequences was shown to enhance the levels of sunlight-induced cyclobutane pyrimidine dimer formation (56) but inhibit the formation of 6 -4 photoproducts (57). Methylation has also resulted in decreased reactivity of both N-methyl and ethyl-N-nitrosourea (58). From these results, it is not clear if there are specific interactions, electronic effects, or structures in the DNA that are responsible for these varied reactivities.…”

Section: Discussionmentioning

confidence: 99%

Cytosine Methylation in a CpG Sequence Leads to Enhanced Reactivity with Benzo[a]pyrene Diol Epoxide That Correlates with a Conformational Change

Weisenberger

Romano

1999

Journal of Biological Chemistry

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Benzo[a]pyrene (B[a]P)is a widespread environmental carcinogen that must be activated by cellular metabolism to a diol epoxide form (BPDE) before it reacts with DNA. It has recently been shown that BPDE preferentially modifies the guanine in methylated 5-CpG-3 sequences in the human p53 gene, providing one explanation for why these sites are mutational hot spots. Using purified duplex oligonucleotides containing identical methylated and unmethylated CpG sequences, we show here that BPDE preferentially modified the guanine in hemimethylated or fully methylated CpG sequences, producing between 3-and 8-fold more modification at this site. Analysis of this reaction using shorter duplex oligonucleotides indicated that it was the level of the (؉)-trans isomer that was specifically increased. To determine if there were conformational differences between the methylated and unmethylated B[a]P-modified DNA sequences that may be responsible for this enhanced reactivity, a native polyacrylamide gel electrophoresis analysis was carried out using DNA containing isomerically pure B[a]P-DNA adducts. These experiments showed that each adduct resulted in an altered gel mobility in duplex DNA but that only the presence of a (؉)-trans isomer and a methylated C 5 to the adduct resulted in a significant gel mobility shift compared with the unmethylated case. Benzo[a]pyrene (B[a]P)1 is a well studied polycyclic aromatic hydrocarbon (for reviews see Refs. 1 and 2) that is ultimately converted by the P450 mixed oxygenase system (1, 3) to one of four diasteromeric diol epoxides: (ϩ)-anti-BPDE, (Ϫ)-anti-BPDE, (ϩ)-syn-BPDE, and (Ϫ)-syn-BPDE (4, 5). The (Ϯ)-anti-BPDE forms are thought to be the most biologically relevant (6), and these enantiomers display very different mutagenicities depending on the host system: the (Ϫ)-anti form is more mutagenic in bacteria, (7) whereas (ϩ)-anti-BPDE is more mutagenic in mammalian cells (7,8) and is widely considered to be the ultimate carcinogenic form of BPDE (9).Regardless of the stereochemistry of anti-BPDE, it is highly reactive, and the major adducts are formed by the cis or trans opening of the epoxide at the C-10 position by the exocyclic amine of guanine (10). The four major guanine adducts are shown in Fig. 1A (11). BPDE also reacts to a lesser extent with the N-6 position of adenine (11) residues to form similar enantiomeric mixtures.The (ϩ)-trans-anti-B[a]P-dGuo adduct is the major form produced following either in vivo or in vitro treatment, and NMR solution studies have shown that this adduct resides in the minor groove of DNA pointing toward the 5Ј-end of the adducted DNA strand (12). The (Ϫ)-trans adduct is also positioned in the minor groove but points in the 3Ј direction (13). Phosphodiesterase digestion of single-stranded DNA oligomers containing the trans adducts have also shown these same adduct orientations (14). NMR studies indicate that both of the cis isomers are more intercalated into the helix, with the (ϩ)-cis pointing toward the minor groove and the (Ϫ)-cis isomers pointing ...

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Effect of 5-methylcytosine as a neighboring base on methylation of DNA guanine by N-methyl-N-nitrosourea

Cited by 20 publications

References 0 publications

CpG methylation potentiates pixantrone and doxorubicin-induced DNA damage and is a marker of drug sensitivity

CpG methylation potentiates pixantrone and doxorubicin-induced DNA damage and is a marker of drug sensitivity

Cytosine methylation determines hot spots of DNA damage in the human P 53 gene

Cytosine Methylation in a CpG Sequence Leads to Enhanced Reactivity with Benzo[a]pyrene Diol Epoxide That Correlates with a Conformational Change

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