Activation‐Induced Deaminase


Activation‐induced deaminase is a simple evolutionary tool that nature has utilised to create a very powerful immune system. Hydrolytic deamination is one of the most ancient of enzymatically catalysed reactions, and yet in the context of deoxyribonucleic acid (DNA) can lead to wanted mutations and chromosomal rearrangements in the humoral immune system, changes in the epigenome and inactivation of foreign DNA. While on the dark side, it can lead to oncogenic mutations and translocations across the whole genome and serve as a conduit for nonmutagenic compounds to become mutagenic.

Key Concepts

  • AID is the ancestor to APOBEC1, and unlike APOBEC1, AID's enzymatic activity is restricted to DNA.
  • AID does not act on cytidine (the RNA nucleoside); hence, it should be classified as activation‐induced deoxy‐cytosine deaminase, or simply activation‐induced deaminase (AID).
  • AID was the first enzyme discovered to actively induce DNA lesions as part of its physiological function.
  • Nearly 70% of all cancer mutations are derived from the AID/APOBEC family.
  • Environmental factors (e.g. oestrogen) can drive AID expression, allowing for nonmutagenic compounds to elicit oncogenic mutations.
  • AID can be expressed in various tissues and lead to local and global DNA instability.
  • AID's ability to deaminate 5‐methyl cytosine can lead to active DNA demethylation and epigenetic reprogramming.
  • The physiological mutation activity of AID can be harnessed in new tools of biotechnology for in vivo genome editing.

Keywords: mutation; DNA cytosine deamination; hypermutation; antibody diversity; DNA demethylation; kataegis; translocation; DNA replication; RNA transcription; evolution

Figure 1. Two stages of antibody diversification in the humoral immune system. During each B‐cell development, the immunoglobulin gene segments (V, D and J) are quasi‐randomly linked to each other forming individual complete antibodies on the surface. The uniqueness of each cell within a large population ensures a broad spectrum of antigen recognising cells (different colour cells). After antigen encounter, those B cells expressing antigen‐binding antibody are activated and initiate the second round of diversification. AID‐dependent SHM introduces point mutations in the antigen‐binding pocket of the antibody (red bars on the lower left), while during CSR, the effector function (i.e. the constant domain) of the antibody is changed (light blue exchanged with brown).
Figure 2. Schematic of AID function. Upon single‐stranded DNA formation, AID gains access to cytosine bases and initiates a hydrolytic deamination. This results in the release of ammonia and the formation of a uracil base.
Figure 3. Context of cytosine deamination for AID. AID prefers to deaminate cytosines that are preceded by a dinucleotide consisting of a weak base (A or T) and a purine (A or G). This sequence context is also known as a WRC motif. Catalytic analysis of the AID‐binding pocket indicated that the smaller modifications on the C5 atom (H, F and CH3 – blue) allowed for deamination of cytosine, while the larger hydroxymethyl (OHCH2 – red) subgroup did not. If the cytosine was bound to a ribose (OH – red) sugar base, no deamination was observed; however, on a deoxyribose (H – blue), AID was showing turnover kinetics.
Figure 4. Schematic of AID. The small, 24 kDa, AID protein is linearly depicted with the N and C‐termini marked. In the centre is the catalytic core, which coordinates the zinc atom binding (purple). The C‐terminal domain (blue) has been shown to be critical for CSR, ubiquitination, subcellular localisation and protein complex binding. The nuclear‐cytoplasmic distribution of AID is dependent on the interplay between the C‐terminal domain and regions near the N‐terminus.
Figure 5. Consequences of AID‐induced deamination. Depending on the cellular context (green), AID activity on dC or 5mC can lead to various local consequences (black), which are part of tissue wide consequences (blue). In all the contexts it is possible for an AID‐induced lesion to become oncogenic and induce mutations and translocation leading to cancer (red).
Figure 6. Evolution of AID and its paralogues. AID originates from the adenosine deaminases acting on tRNA. While it is possible that DNA deaminases have appeared before the vertebrate radiation, the AID/APOBECs seemed to have evolved in vertebrates in correlation with the immune system. The schematic is depicting the evolutionary outgrowth not the size of the deaminase family tree.


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Further Reading

Barreto VM and Magor BG (2011) Activation‐induced cytidine deaminase structure and functions: a species comparative view. Developmental & Comparative Immunology 35 (9): 991–1007. DOI: 10.1016/j.dci.2011.02.005.

Casellas R, Basu U, Yewdell WT, et al. (2016) Mutations, kataegis and translocations in B cells: understanding AID promiscuous activity. Nature Reviews Immunology 16: 164–176.

Conticello SG (2012) Creative deaminases, self‐inflicted damage, and genome evolution. Annals of the New York Academy of Sciences 1267 (1): 79–85. DOI: 10.1111/j.1749-6632.2012.06614.x.

Di Noia JM and Neuberger MS (2007) Molecular mechanisms of antibody somatic hypermutation. Annual Review of Biochemistry 76: 1–22.

Franchini DM, Schmitz KM and Petersen‐Mahrt SK (2012) 5‐Methylcytosine DNA demethylation: more than losing a methyl group. Annual Review of Genetics 46: 419–441.

Petersen‐Mahrt S (2005) DNA deamination in immunity. Immunological Reviews 203 (1): 80–97. DOI: 10.1111/j.0105-2896.2005.00232.x.

Rada C (2015) Mutagenesis by AID: being in the right place at the right time. PLoS Genetics 11: e1005489.

Ramiro A, Reina San‐Martin B, McBride K, et al. (2007) The role of activation‐induced deaminase in antibody diversification and chromosome translocations. Advances in Immunology 94: 75–107.

Stavnezer J (2011) Complex regulation and function of activation‐induced cytidine deaminase. Trends in Immunology 32 (5): 194–201. DOI: 10.1016/, NIH Public Access.

Storb U (2014) Why does somatic hypermutation by AID require transcription of its target genes? Advances in Immunology 122: 253–277.

Zanotti KJ and Gearhart PJ (2016) Antibody diversification caused by disrupted mismatch repair and promiscuous DNA polymerases. DNA Repair 38: 110–116.

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Petersen‐Mahrt, Svend, Conticello, Silvestro, and Munagala, Uday(Jun 2018) Activation‐Induced Deaminase. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024241]