The Journal of Experimental Medicine
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Published 19 August 2002. doi:10.1084/jem.20020851
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© Rockefeller University Press, 0022-1007/2002/8/469/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 4, August 19, 2002 469-480
Evidence for Replicative Repair of DNA Double-Strand Breaks Leading to Oncogenic Translocation and Gene Amplification

Michael J. Difilippantonio1, Simone Petersen2, Hua Tang Chen2, Roger Johnson3, Maria Jasin3, Roland Kanaar4, Thomas Ried1 and André Nussenzweig2

1 Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
2 Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
3 Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
4 Department of Cell Biology and Genetics, Erasmus University Rotterdam, 3000 DR Rotterdam, Netherlands

Address correspondence to Michael J. Difilippantonio, Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892. Phone: 301-435-3991; Fax: 301-402-1204; E-mail: difilipm{at}mail.nih.gov; or André Nussenzweig, Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892. Phone: 301-435-6425; Fax: 301-496-0887; E-mail: andre_nussenzweig{at}nih.gov

Nonreciprocal translocations and gene amplifications are commonly found in human tumors. Although little is known about the mechanisms leading to such aberrations, tissue culture models predict that they can arise from DNA breakage, followed by cycles of chromatid fusion, asymmetric mitotic breakage, and replication. Mice deficient in both a nonhomologous end joining (NHEJ) DNA repair protein and the p53 tumor suppressor develop lymphomas at an early age harboring amplification of an IgH/c-myc fusion. Here we report that these chromosomal rearrangements are initiated by a recombination activating gene (RAG)-induced DNA cleavage. Subsequent DNA repair events juxtaposing IgH and c-myc are mediated by a break-induced replication pathway. Cycles of breakage-fusion-bridge result in amplification of IgH/c-myc while chromosome stabilization occurs through telomere capture. Thus, mice deficient in NHEJ provide excellent models to study the etiology of unbalanced translocations and amplification events during tumorigenesis.

Key Words: nonreciprocal translocations • gene amplification • bridge-fusion breakage • nonhomologous end-joining • tumorigenesis


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