Cytidine deaminases: AIDing DNA demethylation?

Abstract

The presence of 5-methylcytosine (5-mC) in DNA is a vital epigenetic mark in vertebrates. While the enzymes responsible for methylating DNA in vertebrates have been identified, the means by which this mark can be removed are still unclear. Recently, it has been shown that activation-induced cytidine deaminase (AID) contributes to the demethylation of DNA in certain systems. This enzyme has been intensely studied in its role as a key driver of antibody diversification in B cells, but recent observations from early development in zebrafish and mice as well as heterokaryons point to a role beyond immunology. This review takes stock of the reports linking AID and related deaminases to DNA demethylation, and describes the many important questions left to be answered in this field.

Figure 1.

AID can initiate distinct processes through a single enzymatic activity. (A) Deamination of cytosine yields uracil. Excision of uracil by UNG and repair of the subsequent abasic site leads to error-prone repair and SHM when it occurs in the V(D)J regions of the Ig loci. Although error-prone repair also gives rise to mutations at nearby bases, only the outcome of repair on C is shown. (B) Deamination of 5-mC by AID yields thymine. Excision of thymine by either of the mammalian T-G-specific glycosylases (TDG or MBD4) and subsequent error-free replacement with cytosine would yield loss of methylation at that base on one strand. (C) Deamination of cytosine followed by excision of uracil and error-free long-patch BER could lead to replacement and net demethylation of neighboring 5-mCs.