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Kevin M McBride, Yunxiang Mu, Monika Anna Zelazowska, Activation-induced cytidine deaminase mutator activity targeting through phosphorylation, The Journal of Immunology, Volume 200, Issue Supplement_1, May 2018, Page 48.8, https://doi.org/10.4049/jimmunol.200.Supp.48.8
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Abstract
Activation induced cytidine deaminase (AID) initiates immunoglobulin class switch recombination (CSR) and somatic hypermutation (SHM) by deaminating transcribed double stranded DNA to produce U:G mismatches. Subsequent processing of lesions complete SHM or CSR. AID mutator activity predominantly targets the immunoglobulin locus, although "off-target" association also occurs at transcribed regions. The promiscuous targeting has the potential to cause oncogenic mutations, DSBs and chromosome rearrangements and so AID activity must be carefully regulated. How this is accomplished is not completely understood as AID occupancy does not directly correlate with DNA damage, suggesting factors beyond AID association contribute to mutation targeting. It is known that post-translational modifications, in particular AID serine 38 phosphorylation (pS38) regulate AID activity. AID with the inability to be phosphorylated results in deficient CSR and SHM. However, the regulation of pS38 is poorly understood and the contribution of pS38 phosphorylation to off-target AID activity is unknown. Through evaluation of pharmacological inhibitors and activators we identify several that impact AID phosphorylation. We determined that a FDA approved drug, lithium, enhanced AID S38 phosphorylation. Using wild-type B cells and those expressing AID with a S38A mutation, we evaluated the effect of enhanced AID phosphorylation. We find increased off-target mutations, DSBs, and chromosome translocations without an increase in CSR. These studies demonstrate how AID activity can be differentially targeted by phosphorylation to diversify immunoglobulin genes or induce oncogenic lesions.
