PARENT SESSION

Radiation-Induced Genomic Instability

(SY042) The consequences of telomere loss for chromosomal instability.

Sabatier, Laure², Murnane, John ^*,1, ² Laboratoire de Radiobiologie et Oncologie, Fonenay-aux Roses, BP6, France¹ Department of Radiation Oncology, San Francisco, CA, United States

ABSTRACT- Telomere loss has been proposed as an important mechanism for generating the chromosome instability commonly found in cancer cells. A high rate of telomere loss is common even in cancer cells that express telomerase, suggesting that alterations associated with cancer promote telomere instability. We have investigated the consequences of spontaneous or double-strand break-induced telomere loss in mammalian cell lines using a selectable marker gene located adjacent to a telomere. Although telomere loss is accompanied by degradation of the end of the chromosome, these deletions are relatively small. Most chromosome instability due to telomere loss results from sister chromatid fusion, which initiates breakage/fusion/bridge (B/F/B) cycles that continue for many cell generations and result in DNA amplification and large deletions on the end of the chromosome. B/F/B cycles end when the chromosome acquires a new telomere, which occurs primarily through translocations involving either the nonreciprocal transfer or duplication of the arms of other chromosomes. Telomere acquisition also occurs through small duplications involving the subtelomeric region of the other end of the same chromosome, similar to duplications resulting from break-induced replication in yeast. In some cells, a telomere is acquired without detectable duplications or translocations indicating that de novo addition by telomerase may also occur. Although all of these mechanisms for telomere acquisition stabilize the chromosome that loses its telomere, they differ in their consequences for the stability of the genome as a whole. Telomere acquisition involving nonreciprocal translocations results in the loss of a telomere on the donor chromosome, which consequently undergoes additional translocations, isochromosome formation, or complete loss. In contrast, telomere acquisition involving duplications stabilizes the genome, although the large duplications create substantial allelic imbalances. These results demonstrate that the loss of a single telomere can generate a variety of alterations commonly associated with human cancer, not only in the chromosome that loses a telomere, but in other chromosomes as well. Thus, telomere loss is likely to be an important mechanism for chromosome instability in cancer.

Key words: instability, telomere, amplification, translocation