ATM is not required in somatic hypermutation of VH, but is involved in the introduction of mutations in the switch mu region.
Class switch recombination (CSR) and somatic hypermutation (SHM) are mechanistically related processes that share common key factors such as activation-induced cytidine deaminase. We have previously shown a role for ATM (mutated in ataxia-telangiectasia) in CSR. In this paper we show that the frequency, distribution, and nature of base pair substitutions in the Ig variable (V) heavy chain genes in ataxia-telangiectasia patients are largely similar to those in normal donors, suggesting a normal SHM process. Characterization of the third complementarity-determining region in B cells from ataxia-telangiectasia patients also shows a normal V(D)J recombination process. SHM-like mutations could be identified in the switch (S) mu region (up to several hundred base pairs upstream of the S mu -S(alpha) breakpoints) in normal in vivo switched human B cells. In the absence of ATM, mutations can still be found in this region, but at less than half the frequency of that in normal donors. The latter mutations are mainly due to transitions (86% compared with 58% in controls) and are biased to A or T nucleotides. An ATM-dependent mechanism, different from that generating SHM in V genes, is therefore likely to be involved in introducing SHM-like mutations in the S region. ATM may thus be one of the factors that is not shared by the CSR and SHM processes.
Pan-Hammarström
Qiang
Q
Division of Clinical Immunology, IMPI, Karolinska Institute at Huddinge Hospital, Stockholm, Sweden.
Dai
Shujing
S
Zhao
Yaofeng
Y
van Dijk-Härd
Iris F
IF
Gatti
Richard A
RA
Børresen-Dale
Anne-Lise
AL
Hammarström
Lennart
L
D000293:Adolescent; D000328:Adult; D000916:Antibody Diversity / Q000235:genetics; D001260:Ataxia Telangiectasia / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D064007:Ataxia Telangiectasia Mutated Proteins; D001402:B-Lymphocytes / Q000737:chemistry / Q000276:immunology; D001483:Base Sequence; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed; D002648:Child; D002675:Child, Preschool; D022801:Complementarity Determining Regions / Q000032:analysis / Q000235:genetics; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D006801:Humans; D017578:Immunoglobulin Class Switching; D007127:Immunoglobulin Constant Regions / Q000032:analysis / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000032:analysis / Q000235:genetics*; D007144:Immunoglobulin J-Chains / Q000032:analysis / Q000235:genetics; D007134:Immunoglobulin Switch Region / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000032:analysis / Q000235:genetics*; D007142:Immunoglobulin gamma-Chains / Q000032:analysis / Q000235:genetics; D007148:Immunoglobulin mu-Chains / Q000032:analysis / Q000235:genetics*; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D027041:Somatic Hypermutation, Immunoglobulin; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D022801:Complementarity Determining Regions; D004268:DNA-Binding Proteins; D007127:Immunoglobulin Constant Regions; D007143:Immunoglobulin Heavy Chains; D007144:Immunoglobulin J-Chains; D007135:Immunoglobulin Variable Region; D007142:Immunoglobulin gamma-Chains; D007148:Immunoglobulin mu-Chains; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases