Disparate roles of ATR and ATM in immunoglobulin class switch recombination and somatic hypermutation.
Class switch recombination (CSR) and somatic hypermutation (SHM) are mechanistically related processes initiated by activation-induced cytidine deaminase. Here, we have studied the role of ataxia telangiectasia and Rad3-related protein (ATR) in CSR by analyzing the recombinational junctions, resulting from in vivo switching, in cells from patients with mutations in the ATR gene. The proportion of cells that have switched to immunoglobulin (Ig)A and IgG in the peripheral blood seems to be normal in ATR-deficient (ATRD) patients and the recombined S regions show a normal "blunt end-joining," but impaired end joining with partially complementary (1-3 bp) DNA ends. There was also an increased usage of microhomology at the mu-alpha switch junctions, but only up to 9 bp, suggesting that the end-joining pathway requiring longer microhomologies (> or =10 bp) may be ATR dependent. The SHM pattern in the Ig variable heavy chain genes is altered, with fewer mutations occurring at A and more mutations at T residues and thus a loss of strand bias in targeting A/T pairs within certain hotspots. These data suggest that the role of ATR is partially overlapping with that of ataxia telangiectasia-mutated protein, but that the former is also endowed with unique functional properties in the repair processes during CSR and SHM.
Pan-Hammarström
Qiang
Q
Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska University Hospital, Huddinge, SE-14186 Stockholm, Sweden. Qiang.Pan-Hammarstrom@ki.se
Lähdesmäki
Aleksi
A
Zhao
Yaofeng
Y
Du
Likun
L
Zhao
Zhihui
Z
Wen
Sicheng
S
Ruiz-Perez
Victor L
VL
Dunn-Walters
Deborah K
DK
Goodship
Judith A
JA
Hammarström
Lennart
L
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics / Q000276:immunology*; D007135:Immunoglobulin Variable Region; D007137:Immunoglobulin alpha-Chains / Q000235:genetics; D007142:Immunoglobulin gamma-Chains / Q000235:genetics; D007148:Immunoglobulin mu-Chains / Q000235:genetics; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics / Q000276:immunology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000276:immunology*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D007135:Immunoglobulin Variable Region; D007137:Immunoglobulin alpha-Chains; D007142:Immunoglobulin gamma-Chains; D007148:Immunoglobulin mu-Chains; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases