International Research Fellowship Program: Relationship of Human p53 and Rb Pathways to the Alternative Lengthening of Telomeres Phenotype

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0602009CesareThe International Research Fellowship Program enables U.S. scientists and engineers to conduct nine to twenty-four months of research abroad. The program's awards provide opportunities for joint research, and the use of unique or complementary facilities, expertise and experimental conditions abroad.This award will support a twenty-four-month research fellowship by Dr. Anthony J. Cesare to work with Dr. Roger R. Reddel at Children's Medical Research Institute in Sydney, Australia.Telomeres are the protein-DNA caps that protect eukaryotic chromosome termini. In human cells, telomere shortening due to successive cellular division results in telomere structural dysfunction and the activation of a permanent state of cell cycle arrest termed replicative senescence (RS). By-pass of RS by any of several means allows a cell to continue to divide until the telomeres become completely eroded, resulting in cell crisis and eventually death. Very rarely, cells escape death by regenerating and maintaining their telomeres. When this occurs, the cell achieves an immortalized state, which is potentially deleterious in humans. One way that human cells maintain their telomeres is through a poorly understood mechanism termed Alternative Lengthening of Telomeres (ALT). Recent data suggest that ALT-positive cells have perpetual, low-levels of telomere dysfunction that would trigger RS in healthy cells. Further, this dysfunction appears to be a necessary component of the ALT mechanism. The goal of this study is to better understand what role the cellular pathways that mediate the response to dysfunctional telomeres play in regard to ALT. To achieve these results the PI will pursue two specific aims. The first is an investigation in ALT-positive cells of the central mediators of telomere dysfunction response, the p53 and Retinoblastoma (Rb) genes. Typically these genes are mutated, or their protein products are otherwise inactivated, in ALT cell lines. The PI will determine if these components possess ALT-inhibitory functions, thereby making their inactivation essential for the ALT phenotype. Second the PI will investigate the extent of telomere dysfunction in ALT cells to determine if it is sufficient to elicit a DNA damage response at the telomere. The Cancer Research Group at CMRI discovered ALT and remains the field leader in this aspect of telomere biology. This project has significant intellectual potential in a wide rage of fields including telomere biology, ALT and cellular immortalization.