Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 279, Issue 49, Pages 51612-51621Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M408135200
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- NIEHS NIH HHS [ES012259] Funding Source: Medline
- NIGMS NIH HHS [GM21422] Funding Source: Medline
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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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