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DNA methylation and cancer

P W Laird1, R Jaenisch

  • 1Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge 02142.

Human Molecular Genetics
|January 1, 1994
PubMed
Summary

DNA methylation changes are common in cancer and contribute to mutations. A model suggests methyltransferase activity, especially under methyl-donor limiting conditions, drives CpG mutagenesis in tumors.

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Area of Science:

  • Epigenetics
  • Cancer Biology
  • Molecular Oncology

Background:

  • DNA methylation alterations are observed in cancer cells, but their causal role is debated.
  • Both DNA hypomethylation and hypermethylation occur, complicating interpretation.
  • DNA methylation is implicated in generating mutations within tumor DNA.

Purpose of the Study:

  • To investigate the role of DNA methylation in cancer mutagenesis.
  • To propose a model where DNA methyltransferase acts as a mutator enzyme.
  • To link DNA methylation patterns to tumor development and cell physiology.

Main Methods:

  • Review of existing studies on DNA methylation patterns in cancer.
  • Analysis of mutation patterns, particularly C-to-T transitions in the p53 gene.
  • Investigation of prokaryotic DNA methyltransferase activity under methyl-donor limiting conditions.

Main Results:

  • Spontaneous deamination of 5-methylcytosine residues contributes to C-to-T transitions in tumor suppressor genes.
  • A model is proposed where methyltransferase-facilitated deamination drives high mutation rates at CpG dinucleotides.
  • Prokaryotic DNA methyltransferase activity increases under methyl-donor limiting conditions, supporting its role as a mutator.

Conclusions:

  • DNA methyltransferase may act as a mutator enzyme, particularly in early tumor development under methyl-donor limiting conditions.
  • This mechanism explains CpG mutagenesis observed in human tumors and aligns with methionine auxotrophy in cancer cells.
  • Methyl deficiency in tumor cells, despite normal/high DNA methyltransferase expression, is consistent with global DNA hypomethylation.

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