Genomic instability is one of the hallmarks of cancer cells. We are studying telomere function to bothunderstand how chromosomes are maintained and to explore their role in the initiation and growth ofcancer cells. Telomeres distinguish natural chromosome ends from double stranded DNA breaks. Theymaintain chromosome stability by protecting chromosome ends from processes that normally occur atbreaks such as fusion, translocation and DNA degradation. Telomeres are maintained by telomerase,which adds the simple sequence repeat TTAGGG onto all ends. In the next five years we will takeadvantage of the telomerase null mouse, mTR-/-, to dissect the role of telomeres in tumor initiation andgrowth. Using this mouse we previously established that under some conditions short telomeres induceapoptosis and thus decrease tumor growth. In other genetic settings, however, short telomeres initiatechromosomal rearrangements and increase tumor formation. We will examine the proteins that influencewhich pathway will predominate in cells that have short, dysfunctional telomeres. We will use shRNAsto knock down the level of specific proteins that signal DNA damage, to determine their role in signalingthe loss of telomere function. We will examine the role of these genes in both cultured cells in vitro andin tumor formation. To identify new proteins that may recognize dysfunctional telomeres we will screenfor shRNAs that interfere with the response to short telomeres. Although telomerase is required for thegrowth of many tumor cells, some cells have mechanisms that maintain telomeres (alternative telomerelengthening , ALT) and allow growth in the absence of telomerase. We will examine which recombinationpathway(s) play a role in the growth of ALT cells and whether interfering with these pathwaysinhibits the growth of mTR-/- tumors. Understanding the role of these ALT pathways in tumors isessential for potential cancer therapeutics since these alternative mechanisms will be selected for inhuman tumors that are treated with telomerase inhibitors. Finally, we will examine the role of telomeraseactivity in stem cells and how that may potentiate stem cell derived tumors. The hedgehog signalingpathway, which is active in many stem cells, is required for the growth of a variety of common humantumors. We will examine whether telomerase is a target of the hedgehog signaling pathway and what roletelomerase activity plays in these stem cell derived tumors.
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