Reactivity of guanine at m5CpG steps in DNA: Evidence for electronic effects transmitted through the base pairs

Arunangshu Das, Kit S. Tang, S. Gopalakrishnan, Michael J. Waring, Maria Tomasz

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33 Scopus citations


Background: Mitomycin C (MC)1 a DNA cross-linking and alkylating agent, targets guanines in the m5CpG sequence with 2-3-fold preference over guanines in unmethylated CpG. Benzo[a]pyrenediolepoxide (BPDE) and several other aromatic carcinogens form guanine adducts with an identical selectivity for m5CpG1 and in certain cancers G to T transversion mutation 'hotspots' in the p53 tumor suppressor gene are more frequent at this sequence than at guanines in other sequences. MC appears suitable to probe the general mechanism of this selectivity. Results: A 162-bp DNA fragment containing C, m5C or f5C (5-fluoro cytosine) at all cytosine positions was cross-linked by MC at guanines in CpG steps. The extent of cross-linking increased in the order f5C < C < m5C. Monoalkylation or cross-linking of duplex 12-mer oligonucleotides containing a single CpG1 f5CpG or m5CpG step gave yields of adducts that increased in the same order. The rates showed a correlation with the Hammett σ constant of the methyl and fluoro substituents of the cytosine. Only the base-pair cytosine substituent influenced reactivity of guanine. Conclusions: The 2-amino group of guanine in the m5CpG sequence of DNA has a greater nucleophilic reactivity with mitomycin than CpG. Evidence is presented for a novel mechanism: transmission of the electron-donating effect of the 5-methyl substituent of the cytosine to guanine through H-bonding of the m5C-G base pair. The results explain the enhanced reaction of BPDE at m5CpG in DNA and the origin of G-T mutational hotspots in the p53 gene in cancer.

Original languageEnglish (US)
Pages (from-to)461-471
Number of pages11
JournalChemistry and Biology
Issue number7
StatePublished - Jul 1999

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry


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