MSH6- or PMS2-deficiency causes re-replication in DT40 B cells, but it has little effect on immunoglobulin gene conversion or on repair of AID-generated uracils

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Abstract

The mammalian antibody repertoire is shaped by somatic hypermutation (SHM) and class switch recombination (CSR) of the immunoglobulin (Ig) loci of B lymphocytes. SHM and CSR are triggered by non-canonical, error-prone processing of G/U mismatches generated by activation-induced deaminase (AID). In birds, AID does not trigger SHM, but it triggersIggene conversion (GC), a ‘homeologous’ recombination process involving theIgvariable region and proximal pseudogenes. Because recombination fidelity is controlled by the mismatch repair (MMR) system, we investigated whether MMR affects GC in the chicken B cell line DT40. We show here thatMsh6−/−andPms2−/−DT40 cells display cell cycle defects, including genomic re-replication. However, althoughIgVλGC tracts in MMR-deficient cells were slightly longer than in normal cells,IgGC frequency, donor choice or the number of mutations per sequence remained unaltered. The finding that the avian MMR system, unlike that of mammals, does not seem to contribute towards the processing of G/U mismatchesin vitrocould explain why MMR is unable to initiateIgGC in this species, despite initiating SHM and CSR in mammalian cells. Moreover, as MMR does not counteract or governIgGC, we report a rare example of ‘homeologous’ recombination insensitive to MMR.

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