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Evidence for replicative repair of DNA double-strand breaks leading to oncogenic translocation and gene amplification.

Difilippantonio MJ, Petersen S, Chen HT, Johnson R, Jasin M, Kanaar R, Ried T, Nussenzweig A - J. Exp. Med. (2002)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. difilipm@mail.nih.gov

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.

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Related in: MedlinePlus

Telomere healing via chromosome capture. Metaphase spreads were hybridized with painting probes specific for chromosomes 3 (green) and 15 (red) as well as a telomere sequence specific PNA probe (white). (A) The telomere for der(12)a is provided by chromosome 15, however, der(15)a requires the capture of a different chromosome, in this case chromosome 3, in order to obtain telomere repeat sequences. (B) Derivative chromosome 15 [der(15)a] with persistent broken chromatids is not protected from degradation by telomere repeats. (C) Telomere-free end fusion can then result in the formation of a dicentric chromosome.
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fig3: Telomere healing via chromosome capture. Metaphase spreads were hybridized with painting probes specific for chromosomes 3 (green) and 15 (red) as well as a telomere sequence specific PNA probe (white). (A) The telomere for der(12)a is provided by chromosome 15, however, der(15)a requires the capture of a different chromosome, in this case chromosome 3, in order to obtain telomere repeat sequences. (B) Derivative chromosome 15 [der(15)a] with persistent broken chromatids is not protected from degradation by telomere repeats. (C) Telomere-free end fusion can then result in the formation of a dicentric chromosome.

Mentions: A combination of painting probes for chromosomes 3 (green) and 15 (red) and a telomere repeat-specific PNA probe (white) was used to determine if the additional material capping der(15)a contained telomere sequences (Fig. 3) . We observed that in those instances when material from another chromosome (i.e., chromosome 3) capped der(15)a, telomere sequences were indeed present (Fig. 3 A). However, when der(15)a was not capped (as in Fig. 2 B, left panel where the end of der(15)a consisted of amplified copies of IgH Cα and c-myc) there was a distinct absence of telomere sequences (Fig. 3 B). Telomere sequences were also observed on the dicentric chromosomes, but as anticipated only at the two centromeric ends, not at the internal fusion point (Fig. 3 C). Thus, the derivative chromosome in which c-myc and IgH are coamplified is eventually stabilized by the capture of telomeric sequences from other chromosomes.


Evidence for replicative repair of DNA double-strand breaks leading to oncogenic translocation and gene amplification.

Difilippantonio MJ, Petersen S, Chen HT, Johnson R, Jasin M, Kanaar R, Ried T, Nussenzweig A - J. Exp. Med. (2002)

Telomere healing via chromosome capture. Metaphase spreads were hybridized with painting probes specific for chromosomes 3 (green) and 15 (red) as well as a telomere sequence specific PNA probe (white). (A) The telomere for der(12)a is provided by chromosome 15, however, der(15)a requires the capture of a different chromosome, in this case chromosome 3, in order to obtain telomere repeat sequences. (B) Derivative chromosome 15 [der(15)a] with persistent broken chromatids is not protected from degradation by telomere repeats. (C) Telomere-free end fusion can then result in the formation of a dicentric chromosome.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196056&req=5

fig3: Telomere healing via chromosome capture. Metaphase spreads were hybridized with painting probes specific for chromosomes 3 (green) and 15 (red) as well as a telomere sequence specific PNA probe (white). (A) The telomere for der(12)a is provided by chromosome 15, however, der(15)a requires the capture of a different chromosome, in this case chromosome 3, in order to obtain telomere repeat sequences. (B) Derivative chromosome 15 [der(15)a] with persistent broken chromatids is not protected from degradation by telomere repeats. (C) Telomere-free end fusion can then result in the formation of a dicentric chromosome.
Mentions: A combination of painting probes for chromosomes 3 (green) and 15 (red) and a telomere repeat-specific PNA probe (white) was used to determine if the additional material capping der(15)a contained telomere sequences (Fig. 3) . We observed that in those instances when material from another chromosome (i.e., chromosome 3) capped der(15)a, telomere sequences were indeed present (Fig. 3 A). However, when der(15)a was not capped (as in Fig. 2 B, left panel where the end of der(15)a consisted of amplified copies of IgH Cα and c-myc) there was a distinct absence of telomere sequences (Fig. 3 B). Telomere sequences were also observed on the dicentric chromosomes, but as anticipated only at the two centromeric ends, not at the internal fusion point (Fig. 3 C). Thus, the derivative chromosome in which c-myc and IgH are coamplified is eventually stabilized by the capture of telomeric sequences from other chromosomes.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. difilipm@mail.nih.gov

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.

Show MeSH
Related in: MedlinePlus