TELOMERE DYNAMICS IN AN IMMORTAL HUMAN CELL-LINE

The integration of transfected plasmid DNA at the telomere of chromoso me 13 in an immortalized simian virus 40-transformed human cell line p rovided the first opportunity to study polymorphism in the number of t elomeric repeat sequences on the end of a single chromosome. Three sub clones of this cell line were selected for analysis: one with a long t elomere on chromosome 13, one with a short telomere, and one with such extreme polymorphism that no distinct band was discernible. Further s ubcloning demonstrated that telomere polymorphism resulted from both g radual changes and rapid changes that sometimes involved many kilobase s. The gradual changes were due to the shortening of telomeres at a ra te similar to that reported for telomeres of somatic cells without tel omerase, eventually resulting in the loss of nearly all of the telomer e. However, telomeres were not generally lost completely, as shown by the absence of polymorphism in the subtelomeric plasmid sequences. Ins tead, telomeres that were less than a few hundred base pairs in length showed a rapid, highly heterogeneous increase in size. Rapid changes in telomere length also occurred on longer telomeres. The frequency of this type of change in telomere length varied among the subclones and correlated with chromosome fusion. Therefore, the rapid changes in te lomere length appeared occasionally to result in the complete loss of telomeric repeat sequences. Rapid changes in telomere length have been associated with telomere loss and chromosome instability in yeast and could be responsible for the high rate of chromosome fusion observed in many human tumor cell lines.