Evidence for replicative repair of DNA double-strand breaks leading to oncogenic translocation and gene amplification.
J Exp Med
; 196(4): 469-80, 2002 Aug 19.
Article
em En
| MEDLINE
| ID: mdl-12186839
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias do Timo
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Translocação Genética
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Dano ao DNA
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Linfoma de Células B
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Proteínas Proto-Oncogênicas c-myc
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Cadeias Pesadas de Imunoglobulinas
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DNA Helicases
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Antígenos Nucleares
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Proteínas de Ligação a DNA
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Reparo do DNA
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
J Exp Med
Ano de publicação:
2002
Tipo de documento:
Article
País de afiliação:
Estados Unidos