Regulation of the rate of human telomere shortening

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DESCRIPTION (provided by applicant): The long-term objectives of my research are to determine the molecular mechanism regulating telomere shortening in human cells. Due to incomplete DNA replication of linear chromosomes, telomere length continuously shortens as cell divides. Normal cells stop dividing and reach senescence when telomeres are short. Cancer cells are able to maintain their telomere length and divide indefinitely. Decreasing the rate of telomere shortening in normal cells would increase cell life span, while increasing this rate in cancer cells would accelerate cancer cells going into crisis and further stop cancer progression. Therefore, exploring the molecular mechanisms regulating telomere shortening will have major impacts on both extending the functional life span of normal cells and cancer therapy. The specific aims of the research proposal are: (i) to measure the size of telomere overhang at leading and lagging strands in normal human diploid cells and telomerase-positive cells. (ii) to determine the contribution of Okazaki fragment size to telomere shortening rate by directly measuring Okazaki fragment size in vivo and using in vitro DNA replication system respectively; (iii) to investigate the telomere end-replication problem using an in vitro linear DNA replication system.