ДНҚ-да мутация тудыратын фермент

Enzyme that creates mutations in DNA

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 leads to B cell lymphoma.

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 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 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 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. 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.

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.