The Journal of Experimental Medicine
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Published online 3 January 2006 doi:10.1084/jem.20050595
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 1, 99-110
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ARTICLE

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

Qiang Pan-Hammarström1, Aleksi Lähdesmäki1, Yaofeng Zhao1, Likun Du1, Zhihui Zhao1, Sicheng Wen1, Victor L. Ruiz-Perez2, Deborah K. Dunn-Walters3, Judith A. Goodship2, and Lennart Hammarström1

1 Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska University Hospital, Huddinge, SE-14186 Stockholm, Sweden
2 Institute of Human Genetics, Newcastle University, Newcastle-upon-Tyne NE1 3B2, England, UK
3 Dept. of Immunobiology, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, England, UK

CORRESPONDENCE Qiang Pan-Hammarström: Qiang.Pan-Hammarstrom{at}ki.se

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 µ-{alpha} switch junctions, but only up to 9 bp, suggesting that the end-joining pathway requiring longer microhomologies (≥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.

Abbreviations used: AID, activation-induced cytidine deaminase; A-T, ataxia-telangiectasia; ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia and Rad3-related protein; ATRD, ATR-deficient; ATRIP, ATR-interacting protein; C, constant; CSR, class switch recombination; DSB, double-strand break; HR, homologous recombination; NHEJ, nonhomologous end joining; PIKK, phosphoinositol 3-kinase–like kinase; S, switch; SHM, somatic hypermutation; ssDNA, single-stranded DNA; V, variable; VH, Ig variable heavy chain.


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