C.K. Sanders, K.B. Blagoev and E.H. Goodwin

Normal human somatic cells have little or no telomerase activity. Consequently their telomeres grow shorter with each cell division. These cells senesce when their telomeres become too short to protect chromosome ends. In contrast to normal cells, nearly all human tumors avoid senescence by maintaining adequate telomere length. About 85% of tumors reactivate telomerase, and ~15% utilize a poorly understood mechanism called "alternative lengthening of telomeres (ALT)" that is associated with elevated recombination rates particularly within telomeric DNA. That telomerase activity is prevalent in most tumors, yet absent in normal cells, has led to ongoing efforts to test telomerase inhibitors as selective anti-cancer agents. A significant concern with this approach is that tumor cells may escape telomerase inhibition by activating the ALT pathway of telomere maintenance. The several available telomerase inhibitors work through different mechanisms, so conceivably they may affect telomeric recombination rates differently so as to either promote or impede the emergence of ALT. Radiation and some chemotherapeutic drugs, especially those that damage DNA, also are likely to affect recombination. We are investigating these possibilities by developing experimental methods to quantify telomeric recombination, and mathematical methods to connect altered recombination rates to cellular proliferation. These methods will help to evaluate the potential for success of anti-telomerase therapies.

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