Known components of the immunoglobulin A:T mutational machinery are intact in Burkitt lymphoma cell lines with G:C bias.

ABSTRACT

The basis for mutations at AT base pairs in immunoglobulin hypermutation and defining how AID interacts with the DNA of the immunoglobulin locus are major aspects of the immunoglobulin mutator mechanism where questions remain unanswered. Here, we examined the pattern of mutations generated in mice deficient in various DNA repair proteins implicated in AT mutation and found a previously unappreciated bias at GC base pairs in spectra from mice simultaneously deficient in DNA mismatch repair and uracil DNA glycosylase. This suggests a strand-biased DNA transaction for AID delivery which is then masked by the mechanism that introduces AT mutations. Additionally, we asked if any of the known components of the AT mutation machinery underscore the basis for the paucity of AT mutations in the Burkitt lymphoma cell lines, Ramos and BL2. Ramos and BL2 cells were proficient in MSH2/MSH6-mediated mismatch repair, and express high levels of wild-type, full-length DNA polymerase eta. In addition, Ramos cells have high levels of uracil DNA glycosylase protein and are proficient in base excision repair. These results suggest that Burkitt lymphoma cell lines may be deficient in an unidentified factor that recruits the machinery necessary for AT mutation or that AID-mediated cytosine deamination in these cells may be processed by conventional base excision repair truncating somatic hypermutation at the GC phase. Either scenario suggests that cytosine deamination by AID is not enough to trigger AT mutation, and that additional unidentified factors are required for full spectrum hypermutation in vivo.