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DNA Damage and Cellular Stress Responses

The Loss of a Single Telomere Can Result in Instability of Multiple Chromosomes in a Human Tumor Cell Line

¹ Laboratoire de Radiobiologie et Oncologie, Commissariat à l'Energie Atomique, Fontenay-aux Roses, France and ² Radiation Oncology Research Laboratory, University of California, San Francisco, California

Requests for reprints: John P. Murnane, Radiation Oncology Research Laboratory, University of California, San Francisco, 1855 Folsom Street, MCB 200, San Francisco, CA 94103. Phone: 415-476-9083; Fax: 415-476-9069. E-mail: murnane{at}radonc17.ucsf.edu

Spontaneous telomere loss has been proposed as an important mechanism for initiating the chromosome instability commonly found in cancer cells. We have previously shown that spontaneous telomere loss in a human cancer cell line initiates breakage/fusion/bridge (B/F/B) cycles that continue for many cell generations, resulting in DNA amplification and translocations on the chromosome that lost its telomere. We have now extended these studies to determine the effect of the loss of a single telomere on the stability of other chromosomes. Our study showed that telomere acquisition during B/F/B cycles occurred mainly through translocations involving either the nonreciprocal transfer or duplication of the arms of other chromosomes. Telomere acquisition also occurred through small duplications involving the subtelomeric region of the other end of the same chromosome. Although all of these mechanisms stabilized the chromosome that lost its telomere, they differed in their consequences for the stability of the genome as a whole. Telomere acquisition involving nonreciprocal translocations resulted in the loss of a telomere on the donor chromosome, which consequently underwent additional translocations, isochromosome formation, or complete loss. In contrast, telomere acquisition involving duplications stabilized the genome, although the large duplications created substantial allelic imbalances. Thus, the loss of a single telomere can generate a variety of chromosome alterations commonly associated with human cancer, not only on a chromosome that loses its telomere but also on other chromosomes. Factors promoting telomere loss are therefore likely to have an important role in generating the karyotype evolution associated with human cancer.

Key Words: breakage/fusion/bridge cycles • chromosome instability • DNA amplification • isochromosome • nonreciprocal translocation • telomere

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