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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
 -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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