Genetic loss of the ubiquitin ligase RNF126, an AID interacting partner and modifier, affects strand targeting during somatic hypermutation of antibody genes

Abstract

AbstractActivation-induced cytidine deaminase (AID) initiates somatic hypermutation (SHM) and class switch recombination (CSR) in B lymphocytes by catalyzing the introduction of deoxyuracil: deoxyguanine mismatches into the DNA of the transcribed Ig locus. Repair pathways then process these mismatches to produce point mutations in the Ig variable region or double-stranded DNA breaks in the switch region followed by deletional recombination. It has been suggested that post-translational modifications on AID mediate a number of these different decisions, ranging from global targeting (Ig vs the genome), local targeting (variable vs switch region; transcribed vs non-transcribed strand) as well as process-appropriate DNA repair. Here we demonstrate that absence of RNF126, an E3 ligase shown to mono-ubiquitylate AID, results in a specific strand targeting defect in SHM, producing substantial G>C bias; strickingly, loss of RNF126 was also associated with tandem indels within the variable region (JH4 intron) but only a slight increase in the types of chromosomal translocations that are characteristic of deregulated AID. Conversely, these findings suggest that mono-ubiquitination of AID, likely in situ, is necessary for the proper removal of the protein from the non-transcribed strand, thus producing both optimal patterns of SHM and also limiting the number of indels within the target locus.