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 February 2004 Vol 5 No 2 REVIEW


Nature Reviews Molecular Cell Biology 5, 148 -157 (2004); doi:10.1038/nrm1312
 

REPAIRING DNA-METHYLATION DAMAGE

Barbara Sedgwick    about the author

Preface

Methylating agents modify DNA at many different sites, thereby producing lethal and mutagenic lesions. To remove all the main harmful base lesions, at least three types of DNA-repair activities can be used, each of which involves a different reaction mechanism. These activities include DNA-glycosylases, DNA-methyltransferases and the recently characterized DNA-dioxygenases. The Escherichia coli AlkB dioxygenase and the two human homologues, ABH2 and ABH3, represent a novel mechanism of DNA repair. They use iron¨Coxo intermediates to oxidize stable methylated bases in DNA and directly revert them to the unmodified form.

Summary

  • Methylating agents arise endogenously, occur in the environment and are used in chemotherapy. They damage DNA bases at many sites, thereby generating mutagenic and toxic lesions.
  • After exposure of Escherichia coli to a methylating agent, at least three DNA-repair activities are induced that repair the harmful DNA lesions. These activities are AlkA (3-methyladenine-DNA-glycosylase), Ada (O6-methylguanine-DNA-methyltransferase) and AlkB (1-methyladenine-DNA-dioxygenase). These activities are conserved from bacteria to humans.
  • AlkA excises 3-methyladenine and several other damaged bases from DNA, thereby generating abasic sites, whereas Ada directly demethylates O6-methylguanine and O4-methylthymine by transferring the methyl groups onto itself in a suicidal action.
  • AlkB and two human homologues were recently characterized as alpha-ketoglutarate-Fe2+-dependent dioxygenases. They use an iron¨Coxo intermediate to oxidize the methyl groups of 1-methyladenine and 3-methylcytosine in DNA. The methyl groups are released as formaldehyde and the damaged bases directly revert to adenine and cytosine.
  • The lesions 1-methyladenine and 3-methylcytosine are generated in single-stranded DNA, so AlkB and its homologues might function at DNA replication forks or sites of transcription. AlkB and human ABH3 might also have a role in RNA repair.

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