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Oxidative Demethylation of DNA
Author(s) -
Lindahl Tomas,
Sedgwick Barbara
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a205-d
Subject(s) - alkb , dna glycosylase , dna , dna damage , dna demethylation , enzyme , biochemistry , base excision repair , dna repair , chemistry , methyltransferase , dna methylation , methylation , biology , microbiology and biotechnology , gene , gene expression
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.