Activation-induced cytidine deaminase

Activation-induced cytidine deaminase, also known as AICDA and AID, is a 24 kDa is_associated_with::enzyme which in humans is encoded by the AICDA is_associated_with::gene. It creates mutations in is_associated_with::DNA by is_associated_with::deamination of is_associated_with::cytosine base, which turns it into is_associated_with::uracil (which is recognized as a is_associated_with::thymine). In other words, it changes a C:G base pair into a U:G mismatch. The cell's is_associated_with::DNA replication machinery recognizes the U as a T, and hence C:G is converted to a T:A base pair. During is_associated_with::germinal center development of is_associated_with::B lymphocytes, AID also generates other types of mutations, such as C:G to A:T. The mechanism by which these other mutations are created is not well-understood.

In B cells in the is_associated_with::lymph nodes, AID causes mutations that produce antibody diversity, but that same mutation process leads to is_associated_with::B-cell lymphoma.

Function
This gene encodes a DNA-editing deaminase that is a member of the is_associated_with::cytidine deaminase family. The protein is involved in somatic hypermutation, gene conversion, and class-switch recombination of immunoglobulin genes.

AID is currently thought to be the master regulator of secondary is_associated_with::antibody diversification. It is involved in the initiation of three separate immunoglobulin (Ig) diversification processes:
 * 1) is_associated_with::Somatic hypermutation (SHM), in which the antibody genes are minimally mutated to generate a library of antibody variants, some of which with higher affinity for a particular antigen and any of its close variants
 * 2) is_associated_with::Class switch recombination (CSR), in which B cells change their expression from IgM to IgG or other immune types
 * 3) is_associated_with::Gene conversion (GC) a process that causes mutations in antibody genes of chickens, pigs and some other vertebrates.

AID has been shown is_associated_with::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 is_associated_with::transgenes that have been integrated into the is_associated_with::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 is_associated_with::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.


 * 1) The U:G mismatch is replicated across creating two daughter species, one that remains unmutated and one that undergoes a C => T transition mutation. (U is analogous to T in DNA and is treated as such when replicated).
 * 2) The uracil may be excised by is_associated_with::uracil-DNA glycosylase (UNG), resulting in an abasic site. This abasic site (or AP, apurinic/apyrimidinic) may be copied by a translesion synthesis DNA polymerase such as is_associated_with::DNA polymerase eta, resulting in random incorporation of any of the four is_associated_with::nucleotides, i.e. A, G, C, or T. Also, this abasic site may be cleaved by apurinic is_associated_with::endonuclease (APE), creating a break in the is_associated_with::deoxyribose is_associated_with::phosphate backbone. This break can then lead to normal DNA repair, or, if two such breaks occur, one on either strand a staggered double-strand break can be formed (DSB). It is thought that the formation of these DSBs in either the switch regions or the Ig variable region can lead to CSR or GC, respectively.
 * 3) The U:G mismatch may also be recognized by the is_associated_with::DNA mismatch repair (MMR) machinery, to be specific by the MutSα(alpha) complex. MutSα is a is_associated_with::heterodimer consisting of is_associated_with::MSH2 and is_associated_with::MSH6. This heterodimer is able to recognize mostly single-base distortions in the DNA backbone, consistent with U:G DNA mismatches. The recognition of U:G mistmatches by the MMR proteins is thought to lead to processing of the DNA through exonucleolytic activity to expose a single-strand region of DNA, followed by error prone DNA polymerase activity to fill in the gap. These error-prone polymerases are thought to introduce additional mutations randomly across the DNA gap. This allows the generation of mutations at AT base pairs.

Clinical significance
Defects in this gene are associated with is_associated_with::Hyper-IgM syndrome type 2.