Activation-induced (cytidine) deaminase

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Activation-induced (DNA-cytosine) deaminase (AID) is a 24 kDa enzyme that creates mutations in DNA.[1]

AID removes the amino group from a cytosine base, turning it into a 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, 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 lymph nodes, AID causes mutations that produce antibody diversity, but that same mutation process leads to B-cell lymphoma.[2]

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:

  1. 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. Class switch recombination (CSR), in which B cells change their expression from IgM to IgG or other immune types
  3. 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,[3] and has been shown to require active transcription in order to exert its deaminating activity.[4][5][6] 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[edit]

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 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.
  3. 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.

See also[edit]

References[edit]

  1. ^ "Q9GZX7 (AICDA_HUMAN)". Retrieved 26 January 2013. 
  2. ^ Georg Lenz and Louis M. Staudt (2010). "Aggressive Lymphomas". N Engl J Med 362 (15): 1417–29. doi:10.1056/NEJMra0807082. PMID 20393178. 
  3. ^ Bransteitter, R; Pham, P; Scharff, MD; Goodman, MF (Apr 1, 2003). "Activation-induced cytidine deaminase deaminates deoxycytidine on single-stranded DNA but requires the action of RNase". Proceedings of the National Academy of Sciences of the United States of America 100 (7): 4102–7. doi:10.1073/pnas.0730835100. PMC 153055. PMID 12651944. 
  4. ^ Chaudhuri, J; Tian, M; Khuong, C; Chua, K; Pinaud, E; Alt, FW (Apr 17, 2003). "Transcription-targeted DNA deamination by the AID antibody diversification enzyme". Nature 422 (6933): 726–30. doi:10.1038/nature01574. PMID 12692563. 
  5. ^ Sohail, A; Klapacz, J; Samaranayake, M; Ullah, A; Bhagwat, AS (Jun 15, 2003). "Human activation-induced cytidine deaminase causes transcription-dependent, strand-biased C to U deaminations". Nucleic acids research 31 (12): 2990–4. doi:10.1093/nar/gkg464. PMC 162340. PMID 12799424. 
  6. ^ Ramiro, AR; Stavropoulos, P; Jankovic, M; Nussenzweig, MC (May 2003). "Transcription enhances AID-mediated cytidine deamination by exposing single-stranded DNA on the nontemplate strand". Nature immunology 4 (5): 452–6. doi:10.1038/ni920. PMID 12692548.