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- Title
Oxidative Demethylation of DNA.
- Authors
Lindahl, Tomas; Sedgwick, Barbara
- Abstract
Oxidative demethylation of DNA Non-enzymatic methylation of DNA by alkylating agents such as MMS occurs at several sites, but not at the 5 position of cytosine. Instead, the main cytotoxic lesions are 3-methyladenine, and in single-stranded regions of DNA also 1-methyladenine and 3-methylcytosine. The latter lesions are repaired by direct damage reversal by AlkB in E.coli, and ABH2 and ABH3 in mammalian cells. These related enzymes employ Fe(II) and 2-oxoglutarate as cofactors and release the methyl moiety as formaldehyde. There are six additional AlkB-like enzymes in mammalian cells, (ABH1 and ABH4-8) with currently unclear functions, and the enzymes are distantly related to the large group of JmjC proteins. The abundant 3-methyladenine lesion is excised by a single DNA glycosylase, AAG, in mammalian cells to initiate base excision-repair. Down-regulation of AAG with siRNA in human cancer cell lines confers cellular hypersensitivity to alkylating agents such as temozolomide. Similar work is in progress with ABH2.
- Subjects
CHEMICAL processes; DNA; ALKYLATING agents; ENZYMES; PROTEINS
- Publication
FASEB Journal, 2007, Vol 21, Issue 5, pA205
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fasebj.21.5.a205-d