Mismatch recognition and uracil excision provide complementary paths to both Ig switching and the A/T-focused phase of somatic mutation.
AID-mediated deamination of dC residues within the immunoglobulin locus generates dU:dG lesions whose resolution leads to class-switch recombination and somatic hypermutation. The dU:dG pair is a mismatch and comprises a base foreign to DNA and is, thus, recognized by proteins from both base excision (uracil-DNA glycosylase, UNG) and mismatch recognition (MSH2/MSH6) pathways. Strikingly, while antibody diversification is perturbed by single deficiency in either UNG or MSH2, combined UNG/MSH2 deficiency leads to a total ablation both of switch recombination and of IgV hypermutation at dA:dT pairs. The initiating dU:dG lesions appear not to be recognized and are simply replicated over. The results indicate that the major pathway for switch recombination occurs through uracil excision with mismatch recognition of dU:dG providing a backup; the second phase of hypermutation (essentially introducing mutations solely at dA:dT pairs) is triggered by mismatch recognition of the dU:dG lesion with uracil excision providing a backup.
Rada
Cristina
C
Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, United Kingdom. car@mrc-lmb.cam.ac.uk
Di Noia
Javier M
JM
Neuberger
Michael S
MS
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007136:Immunoglobulins / Q000235:genetics*; D051379:Mice; D051718:MutS Homolog 2 Protein; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D014498:Uracil / Q000378:metabolism*; D051981:Uracil-DNA Glycosidase
D004268:DNA-Binding Proteins; D007135:Immunoglobulin Variable Region; D007136:Immunoglobulins; D011518:Proto-Oncogene Proteins; D014498:Uracil; D045647:DNA Glycosylases; D051981:Uracil-DNA Glycosidase; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein