Epigenetic function of activation-induced cytidine deaminase and its link to lymphomagenesis

Abstract

Activation-induced cytidine deaminase (AID) is essential for somatic hypermutation and class switch recombination of immunoglobulin (Ig) genes during B cell maturation and immune response. Expression of AID is tightly regulated due to its mutagenic and recombinogenic potential, which is known to target not only Ig genes, but also non-Ig genes, contributing to lymphomagenesis. In recent years, a new epigenetic function of AID and its link to DNA demethylation came to light in several developmental systems. In this review, we summarize existing evidence linking deamination of unmodified and modified cytidine by AID to base-excision repair and mismatch repair machinery resulting in passive or active removal of DNA methylation mark, with the focus on B cell biology. We also discuss potential contribution of AID-dependent DNA hypomethylation to lymphomagenesis.

Keywords: B cells; DNA methylation; activation-induced cytidine deaminase; epigenetics; lymphomagenesis.

Figure 1

Schematic representation of the proposed mechanisms for active DNA demethylation. DNMTs catalyze the methylation of cytosine (C) to 5-methyl-C (5mC), which can be deaminated to thymine (T) by AID. The generated mismatch can be repaired by the short-patch BER machinery, restoring C, or by one of the processive repair pathways (long-patch BER or MMR), leading to demethylation of a fragment of DNA. This machinery involving processive DNA polymerases can also repair the uracil:guanine (dU:dG) mismatches generated after C deamination to U. On the other hand, TET-mediated hydroxylation of 5mC generates 5-hydroxymethyl-C (5hmC), which can be deaminated by AID/APOBECs to 5-hydroxymethyl-U (5hmU) and replaced by C through BER. 5hmC can be further oxidized by TETs proteins to 5-formyl-C (5fC) and 5-carboxyl-C (5caC), leading to activation of BER to restore C. Finally, another potential mechanism of active DNA demethylation would involve 5mC deamination to T and TET-mediated oxidation of T to 5hmU, which would be replaced by C through BER, although this model has not been proven as yet.