Disparate roles of ATR and ATM in immunoglobulin class switch recombination and somatic hypermutation

• Published in: The Journal of experimental medicine Vol. 203; no. 1; pp. 99 - 110
• Main Authors: Pan-Hammarström, Qiang, Lähdesmäki, Aleksi, Zhao, Yaofeng, Du, Likun, Zhao, Zhihui, Wen, Sicheng, Ruiz-Perez, Victor L, Dunn-Walters, Deborah K, Goodship, Judith A, Hammarström, Lennart
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 23.01.2006
• Subjects: Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins - genetics; Cell Cycle Proteins - immunology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - immunology; Humans; Immunoglobulin alpha-Chains - genetics; Immunoglobulin Class Switching - genetics; Immunoglobulin Class Switching - immunology; Immunoglobulin gamma-Chains - genetics; Immunoglobulin mu-Chains - genetics; Immunoglobulin Variable Region; Medicin och hälsovetenskap; Mutation; Protein Serine-Threonine Kinases - deficiency; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - immunology; Somatic Hypermutation, Immunoglobulin - genetics; Somatic Hypermutation, Immunoglobulin - immunology; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - immunology
• ISSN: 0022-1007; 1540-9538; 1892-1007
• DOI: 10.1084/jem.20050595

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.