title: 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.
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 triggers Ig gene conversion (GC), a 'homeologous' recombination process involving the Ig variable 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 that Msh6(-/-) and Pms2(-/-) DT40 cells display cell cycle defects, including genomic re-replication. However, although IgVλ GC tracts in MMR-deficient cells were slightly longer than in normal cells, Ig GC 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 mismatches in vitro could explain why MMR is unable to initiate Ig GC in this species, despite initiating SHM and CSR in mammalian cells. Moreover, as MMR does not counteract or govern Ig GC, we report a rare example of 'homeologous' recombination insensitive to MMR.
authors: Institut de Recherches Cliniques de Montréal, Division of Immunity and Viral Infections, Montréal, H2W 1R7 Québec, Canada.
authors: Vanina A
authors: VA
authors: Campo
authors: Anne-Marie
authors: AM
authors: Patenaude
authors: Svenja
authors: S
authors: Kaden
authors: Lori
authors: L
authors: Horb
authors: Daniel
authors: D
authors: Firka
authors: Josef
authors: J
authors: Jiricny
authors: Javier M
authors: JM
authors: Di Noia
mesh_terms: D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002460:Cell Line; D053144:Cell Nucleus Shape; D049109:Cell Proliferation; D002645:Chickens / Q000235:genetics*; D003564:Cytidine Deaminase / Q000378:metabolism*; D053843:DNA Mismatch Repair; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D005785:Gene Conversion; D059765:Homologous Recombination; D007136:Immunoglobulins / Q000235:genetics*; D014498:Uracil / Q000378:metabolism*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D004268:DNA-Binding Proteins; D007136:Immunoglobulins; D014498:Uracil; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase