Activation-induced cytidine deaminase, also known as AICDA, AID and single-stranded DNA cytosine deaminase, is a 24 kDa enzyme which in humans is encoded by the AICDA gene. It creates mutations in DNA by deamination of cytosine base, which turns it into uracil (which is recognized as a thymine). In other words, it changes a C:G base pair into a U:G mismatch. The cell's DNA replication machinery recognizes the U as a T, and hence C:G is converted to a T:A base pair. During germinal center development of B lymphocytes, error-prone DNA repair following AID action also generates other types of mutations, such as C:G to A:T. AID is a member of the APOBEC family. In B cells in the lymph nodes, AID causes mutations that produce antibody diversity, but that same mutation process can also lead to B cell lymphoma.

Function

This gene encodes a DNA-editing deaminase that is a member of the cytidine deaminase family. The protein is involved in somatic hypermutation, gene conversion, and class-switch recombination of immunoglobulin genes in B cells of the immune system. AID is currently thought to be the master regulator of secondary antibody diversification. It is involved in the initiation of three separate immunoglobulin (Ig) diversification processes: AID has been shown in vitro to be active on single-strand DNA, and has been shown to require active transcription in order to exert its deaminating activity. The involvement of Cis-regulatory factors is suspected as AID activity is several orders of magnitude higher in the immunoglobulin "variable" region than other regions of the genome that are known to be subject to AID activity. This is also true of artificial reporter constructs and transgenes that have been integrated into the genome. A recent publication suggests that high AID activity at a few non-immunoglobulin targets is achieved when transcription on opposite DNA strands converges due to super-enhancer activity. Recently, AICDA has been implicated in active DNA demethylation. AICDA can deaminate 5-methylcytosine, which can then be replaced with cytosine by base excision repair.

Mechanism

AID is believed to initiate SHM in a multi-step mechanism. AID deaminates cytosine in the target DNA. Cytosines located within hotspot motifs are preferentially deaminated (WRCY motifs W=adenine or thymine, R=purine, C=cytosine, Y=pyrimidine, or the inverse RGYW G=guanine). The resultant U:G (U= uracil) mismatch is then subject to one of a number of fates. The level of AID activity in B cells is tightly controlled by modulating AID expression. AID is induced by transcription factors TCF3 (E47), HoxC4, Irf8 and Pax5, and inhibited by PRDM1 (Blimp1) and Id2. At the post-transcriptional level of regulation, AID expression is silenced by mir-155, a small non-coding microRNA controlled by IL-10 cytokine B cell signalling.

Clinical significance

Defects in this gene are associated with Hyper-IgM syndrome type 2. In certain haematological malignancies such as follicular lymphoma persistent AID expression has been linked to lymphomagenesis.