Telomere maintenance by Werner syndrome family proteins.

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DESCRIPTION (provided by applicant): We will explore connections between telomere biology and disease in the Werner premature aging syndrome, using yeast and cultured human cells as model systems. Telomere shortening accompanies but plays an uncertain causal role in human aging. In contrast, it is clear that prevention of telomere shortening is required for the growth of most cancers. Werner syndrome is characterized by premature features of aging and by elevated rates of cancer, and is caused by loss of the RecQ-family helicase/exonuclease WRN. Evidence is accumulating that Werner cells have telomere defects, which might contribute to the premature aging and elevated cancer incidence, and WRN (and other RecQ helicases) may function in the repair of shortened telomeres. We will dissect the established role of the yeast RecQ homologue, Sgslp, in telomere maintenance. We will map the domains of Sgslp that, in yeast cells lacking telomerase, are required to prevent rapid senescence and telomere shortening, as well as defects in survivors of senescence. We will test alternative mechanisms to explain these defects, including defects in recombination or the formation of G-DNA structures at telomeres. We will also screen for other genetic factors that cooperate with Sgslp in telomere maintenance, including the generation of recombination dependent survivors of senescence. The role in human cells of the mechanisms revealed by studies in yeast, particularly those involving homologous recombination, will be tested by performing experiments in senescing human cultured cells, including those with mutations in WRN. These studies should illuminate the function of WRN at human telomeres and improve understanding of the role of telomeres in natural human aging and cancer.