This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Telomeres are essential for chromosome stability. They ensure effective protection of chromosome ends, and are replicated by a dedicated enzyme, the telomerase reverse transcriptase. Telomeres consist of long (2-10kb) repeats of the TTAGGG sequence and end with a150-300 nucleotides-long TTAGGG single stranded overhang. The six protein complex shelterin specifically binds to telomeres, regulates their length and replication, and ensures their protection. The action of telomerase is negatively regulated by shelterin, accounting for stable average telomere length over time, in cells that express the enzyme. The events involved in this regulation are unclear. The central hypothesis of this proposal is that the recruitment of telomerase is regulated by the shelterin complex. The initial objective will be to initially develop and adapt biochemical assay to quantitatively detect telomerase at chromosome ends (Aim 1). These assays will lay the foundation for the analysis of the role of shelterin in the recruitment of the enzyme to chromosome ends (Aim 2). Other non-shelterin components will be analyzed for their potential positive role in telomerase recruitment (Aim 3). The final specific aim of this proposal outlines the goals for the PI's career development, as well as the plan for the inclusion of the PI and laboratory's efforts into the RCMI Gene Center's goals at Hunter College. The understanding of how telomerase is regulated at its site of action is relevant to cancer at the cellular level. All cancer cells have ultimately activated a mechanism of telomere maintenance with provides them with infinite replicative potential. In the absence of telomere maintenance during cell division, human cells eventually cease to divide, a process called senescence, which is an important tumor suppressor mechanism. Therefore, the proposed work will have high impact on human health.
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