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61 Michael Neuberger Med Res Council, Cambridge, UK |
Background: Many pathways in living organisms are devoted to repairing any modifications that occur to the bases in DNA or changes to its sequence since such changes usually lead to mutations that are deleterious and can predispose to cancer. Recent work, however, has revealed physiological programs of directed attack of DNA, which underpin distinct pathways in innate and adaptive immunity. In both cases, the attack involves deamination of deoxycytidine, leading to the production of deoxyuridine. Since uracil is a base that is that is foreign to DNA (being usually restricted to RNA), the generation of a deoxyuridine lesion in DNA acts as a tag that is recognized by DNA repair enzymes. In the adaptive immune system, DNA deamination acts as an initiating trigger for the generation of antibody diversity and in the class switch recombination necessary for the production high affinity IgG antibodies. Targeted deamination of dC?dU in the immunoglobulin locus is performed by the AID enzyme. Deamination within the immunoglobulin variable (IgV) gene are resolved by pathways that lead to changes in the DNA sequence and thereby generate IgV gene sequence diversity. These mutations (somatic hypermutation) underpin the production of high affinity antibodies. Deamination that occurs within the immunoglobulin switch region is resolved by a process involving deletional recombination and this recombination (class-switch recombination) mediates the change in immunoglobulin isotype from IgM to IgG, IgE, or IgA. In the innate immune system, dC?dU deamination is catalyzed by APOBEC3G and is directly targeted to the first strand cDNA intermediate of the retroviral replication cycle. Such deamination not only underpins a major pathway of host restriction (which the HIV Vif protein seves to antagonise) but also contributes to HIV hypermutation. Conclusions: Thus, deamination of deoxycytidine in DNA underpins an innate pathway of restriction of retroviral infection as well as the production of high affinity antigen-specific IgG antibodies.
