Evidence for replicative repair of DNA double-strand breaks leading to oncogenic translocation and gene amplification.
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.
Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. difilipm@mail.nih.gov
Michael J
MJ
Difilippantonio
Simone
S
Petersen
Hua Tang
HT
Chen
Roger
R
Johnson
Maria
M
Jasin
Roland
R
Kanaar
Thomas
T
Ried
André
A
Nussenzweig
D000818:Animals; D034961:Antigens, Nuclear; D001483:Base Sequence; D004249:DNA Damage; D004265:DNA Helicases; D004260:DNA Repair; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005784:Gene Amplification; D015321:Gene Rearrangement; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D000072200:Ku Autoantigen; D016393:Lymphoma, B-Cell / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology; D009857:Oncogenes; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D016615:Telomere; D013953:Thymus Neoplasms / Q000235:genetics*; D014178:Translocation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D007143:Immunoglobulin Heavy Chains; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; C499308:Rag2 protein, mouse; D016159:Tumor Suppressor Protein p53; C064655:V(D)J recombination activating protein 2; D004265:DNA Helicases; C106893:XRCC5 protein, human; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen