Evidence for replicative repair of DNA double-strand breaks leading to oncogenic translocation and gene amplification Journal Article
| Authors: | Difilippantonio, M. J.; Petersen, S.; Chen, H. T.; Johnson, R.; Jasin, M.; Kanaar, R.; Ried, T.; Nussenzweig, A. |
| Article Title: | Evidence for replicative repair of DNA double-strand breaks leading to oncogenic translocation and gene amplification |
| Abstract: | 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. |
| Keywords: | controlled study; gene translocation; dna-binding proteins; nonhuman; dna replication; animal cell; mouse; telomere; animals; mice; mice, knockout; dna damage; dna repair; gene amplification; cell protein; animal model; gene product; mice, scid; protein p53; carcinogenesis; dna strand breakage; tumorigenesis; nuclear proteins; oncogenes; lymphoma, b-cell; double stranded dna; gene rearrangement; immunoglobulin gene; immunoglobulin heavy chains; molecular sequence data; lymphoma; gene fusion; tumor suppressor protein p53; genetic stability; chromosome rearrangement; base sequence; translocation, genetic; tumor model; proto-oncogene proteins c-myc; thymus neoplasms; dna helicases; oncogene myc; nonhomologous end-joining; antigens, nuclear; priority journal; article; bridge-fusion breakage; nonreciprocal translocations |
| Journal Title: | Journal of Experimental Medicine |
| Volume: | 196 |
| Issue: | 4 |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Date Published: | 2002-08-19 |
| Start Page: | 469 |
| End Page: | 480 |
| Language: | English |
| DOI: | 10.1084/jem.20020851 |
| PUBMED: | 12186839 |
| PROVIDER: | scopus |
| PMCID: | PMC2196056 |
| DOI/URL: | |
| Notes: | Export Date: 14 November 2014 -- Source: Scopus |
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