Biochemical analysis of hypermutational targeting by wild type and mutant activation-induced cytidine deaminase

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Abstract

The synthesis of high affinity antibodies requires activation-induced cytidine deaminase (AID) to initiate somatic hypermutation and class-switch recombination. Here we investigate AID-catalyzed deamination of C → U on single-stranded DNA and on actively transcribed closed circular double-stranded DNA. Mutations are initially favored at canonical WRC (W = A or T, R = A or G) somatic hypermutation hot spot motifs, but over time mutations at neighboring non-hot spot sites increase creating random clusters of mutated regions in a seemingly processive manner. N-terminal AID mutants R35E and R35E/R36D appear less processive and have altered mutational specificity compared with wild type AID. In contrast, a C-terminal deletion mutant defective in CSR in vivo closely resembles wild type AID. A mutational spectrum generated during transcription of closed circular double-stranded DNA indicates that wild type AID retains its specificity for WRC hot spot motifs within the confines of a moving transcription bubble while introducing clusters of multiple deaminations predominantly on the nontranscribed strand.

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Bransteitter, R., Pham, P., Calabrese, P., & Goodman, M. F. (2004). Biochemical analysis of hypermutational targeting by wild type and mutant activation-induced cytidine deaminase. Journal of Biological Chemistry, 279(49), 51612–51621. https://doi.org/10.1074/jbc.M408135200

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