TdT-accessible breaks are scattered over the immunoglobulin V domain in a constitutively hypermutating B cell line.
Searching for an in vitro model for somatic hypermutation, we have identified an IgM-expressing Burkitt lymphoma line that constitutively diversifies its immunoglobulin V domain at high rate during culture. As in in vivo, the mutations are largely nucleotide substitutions with the pattern of substitutions revealing a component of the human hypermutation program that is preferentially targeted to G/C residues. The substitutions frequently create stop codons with IgM-loss variants also being generated by V domain-specific deletions and duplications. However, in transfectants expressing terminal deoxynucleotidyl transferase, many IgM-loss variants additionally arise through short nontemplated nucleotide insertions into the V (but not C) domain. Thus, antibody hypermutation is likely accompanied by DNA strand breaks scattered within the mutation domain.
Sale
J E
JE
Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom.
Neuberger
M S
MS
D001402:B-Lymphocytes; D004249:DNA Damage; D004253:DNA Nucleotidylexotransferase / Q000378:metabolism*; D006801:Humans; D007127:Immunoglobulin Constant Regions / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D007146:Immunoglobulin lambda-Chains / Q000235:genetics; D007148:Immunoglobulin mu-Chains / Q000235:genetics; D016254:Mutagenesis, Insertional; D009154:Mutation; D010641:Phenotype; D014407:Tumor Cells, Cultured
D007127:Immunoglobulin Constant Regions; D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D007146:Immunoglobulin lambda-Chains; D007148:Immunoglobulin mu-Chains; D004253:DNA Nucleotidylexotransferase