Telomeres are critical to the maintenance of chromosomal integrity and replication potential. Defective telomeres result in fused chromosomes and a block in chromosome separation during mitosis, while a loss of telomeric DNA sequences below an apparent lower threshold coincides with cell senescence. On the other hand, addition of telomeric repeats to chromosome breakpoints leads to chromosome healing. The elongation of telomeres is regulated by its length and is mediated by telomerase, and enzyme which is also induced by chromosome fragmentation. In the absence of telomerase, each cell division leads to loss of telomeric repeats because DNA polymerase cannot replicate the end of linear DNA molecules. the newly universal presence of telomerase in tumor cells and its infrequent presence in somatic cells suggests that telomerase inhibition may result in selective antitumor activity. However, the current belief is that telomerase inhibitors do not have significant antitumor activity, because telomere shortening due to telomerase inhibition occurs slowly (e.g. 40% shortening after 70 doublings in human B cells) and because cell replication can continue until the pre-existing telomeres are decreased to the critical minimum length. For example, cell death due to silencing of telomerase occurs only after 23-26 doublings. This application proposes to study the effects of anticancer drugs on telomere, and to determine whether telomere integrity and telomerase play a role in drug activity.
