Similarities in sunlight-induced mutational spectra of CpG-methylated transgenes and the p53 gene in skin cancer point to an important role of 5-methylcytosine residues in solar UV mutagenesis

J Mol Biol. 2001 Jan 19;305(3):389-99. doi: 10.1006/jmbi.2000.4322.

Abstract

In the p53 gene of human sunlight-associated skin cancers, 35 % of the mutations involve trinucleotide sequences with the rare base 5-methylcytosine (5'PymCG). In order to determine the involvement of 5-methylcytosine in sunlight-induced mutations, we have analyzed the cII transgene in mouse cells, a mutational target gene that we found is methylated at most CpG sequences. We report that the mutational spectra produced by irradiation with 254 nm UVC radiation and simulated sunlight, respectively, differ most dramatically by the much higher involvement of dipyrimidine structures containing 5-methylcytosine in the solar UV mutation spectrum (32 % versus 9 % of all mutations). A distinct mutational hotspot induced by simulated sunlight occurs at a sequence 5'TmCG and is associated with high levels of cis-syn cyclobutane pyrimidine dimer formation. A comparison of sunlight-induced mutational spectra of the cII and lacI transgenes, as well as the p53 gene in skin tumors, shows that 5-methylcytosine is involved in 25 to 40 % of all mutations in all three systems. The combined data make a strong case that cyclobutane pyrimidine dimers forming preferentially at dipyrimidine sequences with 5-methylcytosine are responsible for a considerable fraction of the mutations induced by sunlight in mammalian cells.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 5-Methylcytosine
  • Animals
  • Bacterial Proteins / genetics
  • Base Sequence
  • Cell Line
  • CpG Islands / genetics*
  • Cytosine / analogs & derivatives
  • Cytosine / metabolism*
  • DNA Methylation / radiation effects*
  • Escherichia coli Proteins*
  • Fibroblasts
  • Genes, p53 / genetics*
  • Humans
  • Lac Operon / genetics
  • Lac Repressors
  • Mice
  • Models, Genetic
  • Molecular Sequence Data
  • Mutagenesis / radiation effects*
  • Pyrimidine Dimers / analysis
  • Pyrimidine Dimers / genetics
  • Pyrimidine Dimers / radiation effects
  • Repressor Proteins / genetics
  • Skin Neoplasms / genetics*
  • Sunlight / adverse effects*
  • Transcription Factors / genetics
  • Transgenes / genetics
  • Ultraviolet Rays / adverse effects
  • Viral Proteins

Substances

  • Bacterial Proteins
  • Escherichia coli Proteins
  • Lac Repressors
  • Pyrimidine Dimers
  • Repressor Proteins
  • Transcription Factors
  • Viral Proteins
  • cII protein, bacteriophage lambda
  • 5-Methylcytosine
  • Cytosine