Activation-induced cytidine deaminase, also known as AICDA, AID and single-stranded DNA cytosine deaminase, is a 24
kDaenzyme which in humans is encoded by the AICDAgene.[5] It creates mutations in
DNA[6][7] 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 leads to
B cell lymphoma.[8]
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.[5][9]
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:
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 than any of its close variants
Class switch recombination (CSR), in which B cells change their expression from IgM to IgG or other immune types
Gene conversion (GC) a process that causes mutations in antibody genes of chickens, pigs and some other vertebrates.
AID has been shown
in vitro to be active on single-strand DNA,[10] and has been shown to require active
transcription in order to exert its deaminating activity.[11][12][13] 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.[14]
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.[15]
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.[16]
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).
The uracil may be excised by
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
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 (APE), creating a break in the
deoxyribosephosphate 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.
The U:G mismatch may also be recognized by the
DNA mismatch repair (MMR) machinery, to be specific by the MutSα(alpha) 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.
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.[17] At the post-transcriptional level of regulation, AID expression is silenced by
mir-155, a small non-coding
microRNA[18][19] controlled by
IL-10 cytokine B cell signalling.[20]
Wedekind JE, Dance GS, Sowden MP, Smith HC (2003). "Messenger RNA editing in mammals: new members of the APOBEC family seeking roles in the family business". Trends Genet. 19 (4): 207–16.
doi:
10.1016/S0168-9525(03)00054-4.
PMID12683974.
Muto T, Muramatsu M, Taniwaki M, Kinoshita K, Honjo T (2001). "Isolation, tissue distribution, and chromosomal localization of the human activation-induced cytidine deaminase (AID) gene". Genomics. 68 (1): 85–8.
doi:
10.1006/geno.2000.6268.
PMID10950930.
Revy P, Muto T, Levy Y, Geissmann F, Plebani A, Sanal O, Catalan N, Forveille M, Dufourcq-Labelouse R, Gennery A, Tezcan I, Ersoy F, Kayserili H, Ugazio AG, Brousse N, Muramatsu M, Notarangelo LD, Kinoshita K, Honjo T, Fischer A, Durandy A (2000). "Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2)". Cell. 102 (5): 565–75.
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10.1016/S0092-8674(00)00079-9.
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Noguchi E, Shibasaki M, Inudou M, Kamioka M, Yokouchi Y, Yamakawa-Kobayashi K, Hamaguchi H, Matsui A, Arinami T (2001). "Association between a new polymorphism in the activation-induced cytidine deaminase gene and atopic asthma and the regulation of total serum IgE levels". The Journal of Allergy and Clinical Immunology. 108 (3): 382–6.
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Martin A, Bardwell PD, Woo CJ, Fan M, Shulman MJ, Scharff MD (2002). "Activation-induced cytidine deaminase turns on somatic hypermutation in hybridomas". Nature. 415 (6873): 802–6.
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Oppezzo P, Vuillier F, Vasconcelos Y, Dumas G, Magnac C, Payelle-Brogard B, Pritsch O, Dighiero G (2003). "Chronic lymphocytic leukemia B cells expressing AID display dissociation between class switch recombination and somatic hypermutation". Blood. 101 (10): 4029–32.
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