The Journal of Experimental Medicine
AbD Serotec: Antibody Detectives
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Published online 7 August 2006 doi:10.1084/jem.20061067
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 9, 2085-2094
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ARTICLE

 The in vivo pattern of AID targeting to immunoglobulin switch regions deduced from mutation spectra in msh2–/– ung–/– mice

Kanmin Xue, Cristina Rada, and Michael S. Neuberger

Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 2QH, UK

CORRESPONDENCE Michael Neuberger: msn{at}mrc-lmb.cam.ac.uk

Immunoglobulin (Ig) class switching is initiated by deamination of C->U within the immunoglobulin heavy chain locus, catalyzed by activation-induced deaminase (AID). In the absence of uracil-DNA glycosylase (UNG) and the homologue of bacterial MutS (MSH)–2 mismatch recognition protein, the resultant U:G lesions are not processed into switching events but are fixed by replication allowing sites of AID-catalyzed deamination to be identified by the resulting C->T mutations. We find that AID targets cytosines in both donor and acceptor switch regions (S regions) with the deamination domains initiating ~150 nucleotides 3' of the I exon start sites and extending over several kilobases (the IgH intronic enhancer is spared). Culturing B cells with interleukin 4 or interferon {gamma} specifically enhanced deamination around S{gamma}1 and S{gamma}2a, respectively. Mutation spectra suggest that, in the absence of UNG and MSH2, AID may occasionally act at the µ switch region in an apparently processive manner, but there is no marked preference for targeting of the transcribed versus nontranscribed strand (even in areas capable of R loop formation). The data are consistent with switch recombination being triggered by transcription-associated, strand-symmetric AID-mediated deamination at both donor and acceptor S regions with cytokines directing isotype specificity by potentiating AID recruitment to the relevant acceptor S region.

Abbreviations used: AID, activation-induced deaminase; MSH, homologue of bacterial MutS; S region, switch region; Sµ, µ switch region; UNG, uracil-DNA glycosylase.


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