![]() The Ig loci possess an intrinsic ability to attract AID activity 10, conferred in part by specialized cis-acting elements that combine transcriptional enhancers with multiple transcription factor-binding sites and can ectopically function to target SHM 11, 12. The preferential targeting of AID to the Ig genes and how AID mutates a small number of additional genomic loci while sparing most others is an area of active research 4, 9. Regulation of AID protein levels and nuclear access restrains both on- and off-target activities, but it is unclear whether they contribute to target specificity 1. Nevertheless, several additional layers of regulation are necessary to control AID oncogenic and cytotoxic activity 8. As deleterious side effects of SHM and CSR, AID can mutate and induce DNA damage outside the Ig loci, in many cases triggering chromosomal translocations 4.ĭNA repair pathways limit off-target mutations and DNA damage by AID 5, 6, 7. This change is mutagenic, but further processing of the deoxyuridines by DNA repair enzymes underpins somatic hypermutation (SHM) and class switch recombination (CSR), which are indispensable for efficient antibody responses 1, 2, 3. AID catalyses the deamination of deoxycytidine to deoxyuridine on single-stranded DNA (ssDNA) 2. The enzyme activation-induced deaminase (AICDA, referred to as AID, encoded by the Aicda gene) initiates genetic modifications at the immunoglobulin ( Ig) genes in activated B cells 1, 2. Thus AID mutagenic activity is determined not by locus occupancy but by a licensing mechanism, which couples AID to transcription elongation. However, mutant AID fails to occupy the corresponding gene bodies and loses association with transcription elongation factors. Both wt AID and mutants with single amino acid replacements in this domain broadly associate with Spt5 and chromatin and occupy the promoter of AID target genes. Here we show that three clustered arginine residues define a functional AID domain required for SHM, CSR, and off-target activity in B cells without affecting AID deaminase activity or Escherichia coli mutagenesis. The mechanisms underlying productive deamination versus non-productive AID targeting are unclear. AID mutates a few hundred other loci, but most AID-occupied genes are spared. ![]() ![]() Activation-induced deaminase (AID) mutates the immunoglobulin ( Ig) genes to initiate somatic hypermutation (SHM) and class switch recombination (CSR) in B cells, thus underpinning antibody responses.
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