Functional antibody genes are assembled by V-D-J joining and then diversified by somatic hypermutation. This hypermutation results from stepwise incorporation of single nucleotide substitutions into the V gene, underpinning much of antibody diversity and affinity maturation. Hypermutation is triggered by activation-induced deaminase (AID), an enzyme which catalyzes targeted deamination of deoxycytidine residues in DNA. The pathways used for processing the AID-generated U:G lesions determine the variety of base substitutions observed during somatic hypermutation. Thus, DNA replication across the uracil yields transition mutations at C:G pairs, whereas uracil excision by UNG uracil-DNA glycosylase creates abasic sites that can also yield transversions. Recognition of the U:G mismatch by MSH2/MSH6 triggers a mutagenic patch repair in which polymerase eta plays a major role and leads to mutations at A:T pairs. AID-triggered DNA deamination also underpins immunoglobulin variable (IgV) gene conversion, ...

Molecular Mechanisms of Antibody Somatic Hypermutation

The evolution of adaptive immune systems.

HIV-1 Accessory Proteins—Ensuring Viral Survival in a Hostile Environment

The immune gene repertoire encoded in the purple sea urchin genome

The AID/APOBECs, a group of cytidine deaminases, represent a somewhat unusual protein family that can insert mutations in DNA and RNA as a result of their ability to deaminate cytidine to uridine. The ancestral AID/APOBECs originated from a branch of the zinc-dependent deaminase superfamily at the beginning of the vertebrate radiation. Other members of the family have arisen in mammals and present a history of complex gene duplications and positive selection. All AID/APOBECs have a characteristic zinc-coordination motif, which forms the core of the catalytic site. The crystal structure of human APOBEC2 shows remarkable similarities to that of the bacterial tRNA-editing enzyme TadA, which suggests a conserved mechanism by which polynucleotides are recognized and deaminated. The AID/APOBECs seem to have diverse roles. AID and the APOBEC3s are DNA mutators, acting in antigen-driven antibody diversification processes and in an innate defense system against retroviruses, respectively. APOBEC1 edits the mRNA for apolipoprotein B, a protein involved in lipid transport. A detailed understanding of the biological roles of the family is still some way off, however, and the functions of some members of the family are completely unknown. Given their ability to mutate DNA, a role for the AID/APOBECs in the onset of cancer has been proposed.

/pdf/the-aid-apobec-family-of-nucleic-acid-mutators-4gg4npyajc.pdf

The AID/APOBEC family of nucleic acid mutators

The AID/APOBEC family (comprising AID, APOBEC1, APOBEC2, and APOBEC3 subgroups) contains members that can deaminate cytidine in RNA and/or DNA and exhibit diverse physiological functions (AID and APOBEC3 deaminating DNA to trigger pathways in adaptive and innate immunity; APOBEC1 mediating apolipoprotein B RNA editing). The founder member APOBEC1, which has been used as a paradigm, is an RNA-editing enzyme with proposed antecedents in yeast. Here, we have undertaken phylogenetic analysis to glean insight into the primary physiological function of the AID/APOBEC family. We find that although the family forms part of a larger superfamily of deaminases distributed throughout the biological world, the AID/APOBEC family itself is restricted to vertebrates with homologs of AID (a DNA deaminase that triggers antibody gene diversification) and of APOBEC2 (unknown function) identifiable in sequence databases from bony fish, birds, amphibians, and mammals. The cloning of an AID homolog from dogfish reveals that AID extends at least as far back as cartilaginous fish. Like mammalian AID, the pufferfish AID homolog can trigger deoxycytidine deamination in DNA but, consistent with its cold-blooded origin, is thermolabile. The fine specificity of its mutator activity and the biased codon usage in pufferfish IgV genes appear broadly similar to that of their mammalian counterparts, consistent with a coevolution of the antibody mutator and its substrate for the optimal targeting of somatic mutation during antibody maturation. By contrast, APOBEC1 and APOBEC3 are later evolutionary arrivals with orthologs not found in pufferfish (although synteny with mammals is maintained in respect of the flanking loci). We conclude that AID and APOBEC2 are likely to be the ancestral members of the AID/APOBEC family (going back to the beginning of vertebrate speciation) with both APOBEC1 and APOBEC3 being mammal-specific derivatives of AID and a complex set of domain shuffling underpinning the expansion and evolution of the primate APOBEC3s.

/pdf/evolution-of-the-aid-apobec-family-of-polynucleotide-deoxy-52tu6eq4u2.pdf

Evolution of the AID/APOBEC Family of Polynucleotide (Deoxy)cytidine Deaminases

The BZLF1 open reading frame of Epstein–Barr virus (EBV) encodes an important transactivator of replication. During latency, transcription of this gene is switched off. HI motifs have been shown to cause negative regulation of the promoter. Using yeast one-hybrid assays, we isolated the E box-binding protein, E2-2, interacting with these motifs. Electrophoretic mobility shift assays demonstrated that E2-2 binds to HIα, HIβ and HIγ, which contain E box consensus binding sites. Deletion of the HI-associated E boxes and overexpression of E2-2 in transfection assays revealed that these elements act as repressors in lymphoid cells. In contrast, in epithelial cells they contribute to the increased responsiveness of the promoter to transactivation by the BZLF1 protein. The data presented are in accord with an alternative and exclusive binding of different cell type- and differentiation-specific factors, such as E2-2, to the HI-associated E boxes in lymphoid and epithelial cells. This implies a role in cell type-specific virus replication.

Cornelia Thomas

Papers

Evolution of the AID/APOBEC Family of Polynucleotide (Deoxy)cytidine Deaminases

The BZLF1 promoter of Epstein-Barr virus is controlled by E box-/HI-motif-binding factors during virus latency.

Short Communication The BZLF1 promoter of Epstein-Barr virus is controlled by E box-/HI-motif-binding factors during virus latency