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TDG excision of fC may be a predominant element of pathways for active DNA demethylation
Author(s) -
Maiti Atanu,
Hwang BorJang,
Armwood Cherece J.,
LuChang ALien,
Drohat Alexander C.
Publication year - 2013
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.27.1_supplement.758.6
Subject(s) - dna demethylation , base excision repair , dna glycosylase , demethylation , dna , dna repair , microbiology and biotechnology , gene , biology , epigenetics , chemistry , biochemistry , dna methylation , gene expression
Base excision repair (BER) is essential for maintaining genetic integrity and for active DNA demethylation, a central element of epigenetic gene regulation. A key player in both processes is thymine DNA glycosylase (TDG), which excises modified forms of 5‐methylcytosine (mC). TDG excises thymine from mutagenic G/T mispairs arising from mC deamination. TDG also excises 5‐formylcytosine (fC) and 5‐carboxylcytosine (caC), oxidized forms of mC generated by Tet enzymes. TDG is essential for embryonic development, reflecting a crucial function in regulating gene expression that likely involves a key step in active DNA demethylation. We used structural, biochemical, and cell‐based methods to understand how TDG attains specificity for excising select forms of modified mC (i.e., T, fC, and caC). We identified a TDG variant that retains fC activity, but lacks detectible caC activity, indicating a fundamental difference in the excision mechanism for these related bases. We used this variant to study the role of TDG in active DNA demethylation in human cells. The results indicate that TDG excision of fC can account for findings that caC is depleted in cells expressing TDG, consistent with the fact that fC is a precursor for Tet‐mediated formation of caC. The results suggest that TDG excision of fC could be a predominant element in a pathway for active DNA demethylation. Supported by the NIH (R01‐GM072711).