DNA amplification by breakage/fusion/bridge cycles initiated by spontaneous telomere loss in a human cancer cell line.
The development of genomic instability is an important step in generating the multiple genetic changes required for cancer. One consequence of genomic instability is the overexpression of oncogenes due to gene amplification. One mechanism for gene amplification is the breakage/fusion/bridge (B/F/B) cycle that involves the repeated fusion and breakage of chromosomes following the loss of a telomere. B/F/B cycles have been associated with low-copy gene amplification in human cancer cells, and have been proposed to be an initiating event in high-copy gene amplification. We have found that spontaneous telomere loss on a marker chromosome 16 in a human tumor cell line results in sister chromatid fusion and prolonged periods of chromosome instability. The high rate of anaphase bridges involving chromosome 16 demonstrates that this instability results from B/F/B cycles. The amplification of subtelomeric DNA on the marker chromosome provides conclusive evidence that B/F/B cycles initiated by spontaneous telomere loss are a mechanism for gene amplification in human cancer cells.
Lo
Anthony W I
AW
Radiation Oncology Research Laboratory, University of California, 1855 Folsom Street, MCB 200, San Francisco, CA 94103, USA.
Sabatier
Laure
L
Fouladi
Bijan
B
Pottier
Géraldine
G
Ricoul
Michelle
M
Murnane
John P
JP
D000705:Anaphase / Q000235:genetics; D015139:Blotting, Southern; D002869:Chromosome Aberrations; D019457:Chromosome Breakage / Q000235:genetics*; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000235:genetics*; D005784:Gene Amplification; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D010957:Plasmids / Q000235:genetics; D016615:Telomere / Q000235:genetics* / Q000378:metabolism; D013937:Thymidine Kinase / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000502:physiology; D001749:Urinary Bladder Neoplasms / Q000235:genetics*
D004273:DNA, Neoplasm; D013937:Thymidine Kinase