Telomere length dynamics and chromosomal instability in cells derived fromtelomerase null mice

To study the effect of continued telomere shortening on chromosome stabilit y, we have analyzed the telomere length of two individual chromosomes (chro mosomes 2 and 11) in fibroblasts derived from wild-type mice and from mice lacking the mouse telomerase RNA (mTER) gene using quantitative fluorescenc e in situ hybridization. Telomere length at both chromosomes decreased with increasing generations of mTER(-/-) mice. At the 6th mouse generation, thi s telomere shortening resulted in significantly shorter chromosome 2 telome res than the average telomere length of all chromosomes. Interestingly, the most frequent fusions found in mTER(-/-) cells were homologous fusions inv olving chromosome 2. Immortal cultures derived from the primary mTER(-/-) c ells showed a dramatic accumulation of fusions and translocations, revealin g that continued growth in the absence of telomerase is a potent inducer of chromosomal instability. Chromosomes 2 and 11 were frequently involved in these abnormalities suggesting that, in the absence of telomerase, chromoso mal instability is determined in part by chromosome-specific telomere lengt h. At Various points during the growth of the immortal mTER(-/-) cells, tel omere length was stabilized in a chromosome-specific manner. This telomere- maintenance in the absence of telomerase could provide the basis for the ab ility of mTER(-/-) cells to grow indefinitely and form tumors.