Reversal of DNA Alkylation Damage by Two Human Dioxygenases

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2002 Dec 18

PMID 12486230

Citations 185

Authors

Tod Duncan

Sarah C Trewick

Pertti Koivisto

Paul A Bates

Tomas Lindahl

Barbara Sedgwick

Affiliations

Soon will be listed here.

Abstract

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.

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