Molecular mechanisms of antibody somatic hypermutation.
Functional antibody genes are assembled by V-D-J joining and then diversified by somatic hypermutation. This hypermutation results from stepwise incorporation of single nucleotide substitutions into the V gene, underpinning much of antibody diversity and affinity maturation. Hypermutation is triggered by activation-induced deaminase (AID), an enzyme which catalyzes targeted deamination of deoxycytidine residues in DNA. The pathways used for processing the AID-generated U:G lesions determine the variety of base substitutions observed during somatic hypermutation. Thus, DNA replication across the uracil yields transition mutations at C:G pairs, whereas uracil excision by UNG uracil-DNA glycosylase creates abasic sites that can also yield transversions. Recognition of the U:G mismatch by MSH2/MSH6 triggers a mutagenic patch repair in which polymerase eta plays a major role and leads to mutations at A:T pairs. AID-triggered DNA deamination also underpins immunoglobulin variable (IgV) gene conversion, isotype class switching, and some oncogenic translocations in B cell tumors.
Di Noia
Javier M
JM
Institut de Recherches Cliniques de Montréal, H2W 1R7 Montréal, Québec, Canada. javier.di.noia@ircm.qc.ca
Neuberger
Michael S
MS
D000818:Animals; D000906:Antibodies; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D005803:Genes, Immunoglobulin; D006801:Humans; D017578:Immunoglobulin Class Switching; D051718:MutS Homolog 2 Protein / Q000378:metabolism; D009154:Mutation; D011995:Recombination, Genetic; D027041:Somatic Hypermutation, Immunoglobulin; D014158:Transcription, Genetic; D014498:Uracil / Q000378:metabolism; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D000906:Antibodies; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D014498:Uracil; D004247:DNA; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase; D051718:MutS Homolog 2 Protein