Activation-induced cytidine deaminase
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. 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 diversification processes:
- Somatic hypermutation, 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 than any of its close variants
- Class switch recombination, in which B cells change their expression from IgM to IgG or other immune types
- Gene conversion a process that causes mutations in antibody genes of chickens, pigs and some other vertebrates.
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. The resultant U:G mismatch is then subject to one of a number of fates.- The U:G mismatch is replicated across creating two daughter species, one that remains unmutated and one that undergoes a C => T transition mutation..
- The uracil may be excised by uracil-DNA glycosylase, resulting in an abasic site. This abasic site may be copied by a translesion synthesis DNA polymerase such as DNA polymerase eta, resulting in random incorporation of any of the four nucleotides, i.e. A, G, C, or T. Also, this abasic site may be cleaved by apurinic endonuclease, creating a break in the deoxyribose 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. 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.
- The U:G mismatch may also be recognized by the DNA mismatch repair machinery, to be specific by the MutSα complex. MutSα is a heterodimer consisting of MSH2 and 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.