Somatic hypermutation: Processivity of the cytosine deaminase AID and error-free repair of the resulting uracils

Abstract

The somatic hypermutation (SHM) process is initiated in activated B lymphocytes by the cytosine DNA deaminase AID creating uracils that are further treated by DNA replication and/or error-prone base excision repair (BER) and/or error-prone mismatch repair (MMR), resulting in mutations at the targeted cytosines, as well as at all four nucleotides neighboring the AID-induced uracil. In this analysis we investigate two issues that are specific to SHM, the processivity of AID in vivo in vertebrate cells versus in cell free assays, and the error-prone versus error-free repair of the AID-induced uracils. Compilation of published data shows that AID is highly processive in vitro, but shows little, although apparently real, processivity in vivo. We postulate that the combined effects of chromatin and associated transcription factors prevent AID from migrating along extensive tracks in vivo. The comparison of mutation loads in Ig genes at cytosines in wild type mice with those in mice with a combined Ung/MMR-deficiency suggests that Ig genes in wild type mice undergo error-free repair of over 47% of the uracils originally created by AID. The uracil glycosylase Ung which is involved in the error-prone repair during SHM is also involved in the error-free repair.