Reversal of DNA alkylation damage by two human dioxygenases.
The Escherichia coli AlkB protein protects against the cytotoxicity of methylating agents by repair of the DNA lesions 1-methyladenine and 3-methylcytosine, which are generated in single-stranded stretches of DNA. AlkB is an alpha-ketoglutarate- and Fe(II)-dependent dioxygenase that oxidizes the relevant methyl groups and releases them as formaldehyde. Here, we identify two human AlkB homologs, ABH2 and ABH3, by sequence and fold similarity, functional assays, and complementation of the E. coli alkB mutant phenotype. The levels of their mRNAs do not appear to correlate with cell proliferation but tissue distributions are different. Both enzymes remove 1-methyladenine and 3-methylcytosine from methylated polynucleotides in an alpha-ketoglutarate-dependent reaction, and act by direct damage reversal with the regeneration of the unsubstituted bases. AlkB, ABH2, and ABH3 can also repair 1-ethyladenine residues in DNA with the release of acetaldehyde.
Duncan
Tod
T
Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire EN6 3LD, United Kingdom.
Trewick
Sarah C
SC
Koivisto
Pertti
P
Bates
Paul A
PA
Lindahl
Tomas
T
Sedgwick
Barbara
B
D000225:Adenine / Q000031:analogs & derivatives* / Q000378:metabolism*; D000071498:AlkB Homolog 1, Histone H2a Dioxygenase; D000478:Alkylation; D000595:Amino Acid Sequence; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D045643:DNA Repair Enzymes; D029968:Escherichia coli Proteins / Q000502:physiology; D006801:Humans; D006899:Mixed Function Oxygenases / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D008969:Molecular Sequence Data
D029968:Escherichia coli Proteins; C036386:3-methylcytosine; C008407:1-methyladenine; D003596:Cytosine; D006899:Mixed Function Oxygenases; C499236:ALKBH1 protein, human; D000071498:AlkB Homolog 1, Histone H2a Dioxygenase; C023164:thymine, 2-oxoglutarate dioxygenase; D045643:DNA Repair Enzymes; D000225:Adenine