Activation-Induced (Cytidine) Deaminase


Activation-Induced (Cytidine) Deaminase

Activation-Induced (Cytidine) Deaminase (AID) is a 24 kDa enzyme that removes the amino group from the cytidine base in DNA.

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), class switch recombination (CSR) and gene-conversion (GC).

AID has been shown in vitro to be active on single stranded DNA [Bransteitter et al. PNAS 100(7):4102-4107] , 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.

Mechanism

AID is believed to initiate SHM in a multi-step mechanism. AID deaminates cytidine in the target DNA. Cytidines located within hotspot motifs are prefferentially deaminated (WRCY motifs W=adenosine or thymidine, R=purine, C=cytidine, Y=pyrimidine, or the inverse RGYW G=guanidine). The resultant U:G (U= uridine) 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. (U is analogous to T in DNA and is treated as such when replicated).
# The uridine may be excised by uracil DNA glycosylase (UDG) resulting in an abasic site. This abasic site (or AP,apurinic/aprimidinic) if replicated across will result in random incorporation of any of the four nucleotides. i.e. A, G, C or T. Alternately this abasic site can be cleaved by apurinic endonuclease (APE) 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 (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 can be recognized by the DNA mismatch repair (MMR) machinery, most notably MutSa(alpha). MutSa 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.


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