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  • Review Article
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Repairing DNA-methylation damage

Nature Reviews Molecular Cell Biology volume 5, pages 148–157 (2004)Cite this article

Key Points

  • 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 α-ketoglutarate-Fe2+-dependent dioxygenases. They use an iron–oxo 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.

Abstract

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–oxo intermediates to oxidize stable methylated bases in DNA and directly revert them to the unmodified form.

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Figure 1: Sites of methylation on the bases and sugar–phosphate backbone of DNA.
Figure 2: Demethylation of stable O-methylated-DNA lesions by the Escherichia coli Ada DNA-methyltransferase.
Figure 3: Oxidative dealkylation of 1-methyladenine and 1-ethyladenine in DNA by Escherichia coli AlkB.
Figure 4: Conserved domains of AlkB-family proteins.

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Acknowledgements

The author would like to thank M. Mitchell for help with the sequence alignment, and T. Duncan, P. Karran, P. Koivisto and T. Lindahl for criticisms of the manuscript.

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Authors and Affiliations

  1. Cancer Research UK London Research Institute, Clare Hall Laboratories, Blanche Lane, South Mimms, Hertfordshire, EN6 3LD, UK

    Barbara Sedgwick

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  1. Barbara Sedgwick
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DATABASES

Entrez

MutT

Dut

Swiss-Prot

AAG

ABH1

ABH3

Ada

AidB

AlkA

AlkB

CYP2E

Ogt

PCNA

Tag

Weizmann institute GeneCards homepage

DEPC-1

LOC121642

Glossary

ADA RESPONSE

The adaptive response of E. coli to methylating agents results from the increased expression of several genes that are regulated by the Ada protein, and is therefore referred to as the Ada response.

METHYL HALIDES

Naturally occurring methyl halides include methyl chloride, methyl bromide and methyl iodide. Methyl chloride is probably the most abundant SN2 methylating agent in the environment.

TRANSITION MUTATION

A mutation that arises by substitution of a pyrimidine by a pyrimidine (cytosine by thymine or vice versa) or a purine by a purine (guanine by adenine or visa versa).

POST-REPLICATIVE MISMATCH REPAIR

This pathway removes mismatched bases from DNA that arise as a result of DNA-replication errors. A long single-stranded oligonucleotide containing the mispaired base is excised from the newly synthesized dna strand, and the gap is refilled by dna polymerase and DNA ligase.

HELIX–TURN–HELIX (HhH) MOTIF

A protein substructure that is composed of two α-helices that are connected by a hairpin loop; it is a signature of a dna-binding motif.

R- AND S- DIASTEREOISOMERS

Stereoisomers have the same molecular constitution but differ in the three-dimensional arrangement of their atomic groupings. The different optical arrangements are referred to as S- and R-. Diastereoisomers have more than one stereoisomeric centre.

BASE EXCISION REPAIR

Bacteria and human cells have seven or eight DNA-glycosylases that excise endogenously damaged bases from dna and initiate base excision repair. The most frequent endpoint of this pathway is the replacement of a single nucleotide, but occasionally longer replacement patches occur.

NUCLEOTIDE EXCISION REPAIR

A significant role of this DNA-repair pathway is the removal of bulky lesions from dna, such as cyclobutyl-pyrimidine dimers that are induced by ultraviolet light. A complex of activities excises a single-stranded oligonucleotide, which contains the lesion, and the gap is filled by DNA polymerase and DNA ligase.

DNA-PHOTOLYASE

DNA-photolyase uses visible light as an energy source to cleave cyclobutyl-pyrimidine dimers (DNA lesions that are formed by the covalent linkage of two adjacent pyrimidines by two carbon–carbon bonds, and that are induced on exposure of DNA to ultraviolet light).

PROLIFERATING-CELL NUCLEAR ANTIGEN

(PCNA). PCNA was first identified as a DNA sliding clamp for replicative polymerases, but is now known to coordinate the organization of protein partners that are involved in many processes, including dna replication, dna repair and cell-cycle control.

PYRIMIDINE-SALVAGE PATHWAY

This pathway is found in several fungi and leads to the conversion of thymidine to uracil and so allows reuse of the pyrimidine ring. Thymidine can be used as a sole source of pyrimidine by these organisms.

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Sedgwick, B. Repairing DNA-methylation damage. Nat Rev Mol Cell Biol 5, 148–157 (2004). https://doi.org/10.1038/nrm1312

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