Abstract
Activation-induced cytidine deaminase (AID) generates U:G mismatches in Ig genes that can be converted into untemplated mutations during somatic hypermutation or DNA double-strand breaks during class switch recombination (CSR). Null mutations in UNG and MSH2 demonstrate the complementary roles of the base excision repair (BER) and mismatch repair pathways, respectively, in CSR. Phosphorylation of AID at serine 38 was previously hypothesized to regulate BER during CSR, as the AID phosphorylation mutant, AID(S38A), cannot interact with APE1, a BER protein. Consistent with these findings, we observe a complete block in CSR in AIDS38A/S38AMSH2-/- mouse B cells that correlates with an impaired mutation frequency at 5'Sμ. Similarly, somatic hypermutation is almost negligible at the JH4 intron in AIDS38A/S38AMSH2-/- mouse B cells, and, consistent with this, NP-specific affinity maturation in AIDS38A/S38AMSH2-/- mice is not significantly elevated in response to NP-CGG immunization. Surprisingly, AIDS38A/S38AUNG-/- mouse B cells also cannot complete CSR or affinity maturation despite accumulating significant mutations in 5'Sμ as well as the JH4 intron. These data identify a novel role for phosphorylation of AID at serine 38 in mismatch repair-dependent CSR and affinity maturation.