We are interested in the mechanisms that regulate telomere length in normal and cancer cells. Telomeres are the structures at chromosome ends that provide stability to chromosomes and allow the complete replication of the ends. Broken chromosomes that lack telomeres undergo fusions that lead to karyotypic abnormality and chromosome instability; characteristics common in cancer cells. Telomere length is normally maintained as an equilibrium between processes that lengthen and those that shorten telomeres. The ribonucleoprotein DNA polymerase, telomerase, specifically elongates telomeres in vivo. Recent evidence suggests that telomerase may be required for the growth of tumors. Thus, telomerase has been proposed as a new target for cancer chemotherapy. To determine if the absence of telomerase inhibits tumor growth or tumor progression, we are generating a telomerase null mouse in collaboration with Dr. Ronald DePinho. The experiments proposed here will determine whether telomerase is required for tumor induction and for sustained tumor growth. If telomerase is required for sustained tumor growth, tumors lacking telomerase will progress more slowly or perhaps regress, compared to telomerase expressing tumors. Thus or studies in mice will determine whether anti-telomerase drugs may be effective cancer therapeutics. We will look directly for potential recombination mediated telomerase bypass pathways that may lead to telomerase independent tumors. Finally, a telomerase null mouse will help identify potential side effects of telomerase inhibitors, which will need to be addressed in pre-clinical studies.
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