We will explore connections between telomeres biology and diseases in the Werner premature aging syndrome, using mouse and yeast 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 and Bloom syndrome are characterized by premature features of aging and by elevated rates of cancers. The syndromes are caused by loss of the related RecQ-family helicases WRN and BLM, respectively. 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 maintenace. 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 surivivors of senescence. We will test alternative mechanisms to explain these defects, including inappropriate 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. We will also examine the function of WRN and BLM in mice that have shortened telomeres due to genetic inactivation of telomerase. We will ask whether mice that lack telomerase and WRN and BLM together develop earlier, more profound or even different defects than mice that simply lack telomerase alone or WRN and BLM together. Atrophy and apoptosis in highly proliferative tissues, including the gonads, gastrointestinal system and skin, will be examined. Rates of telomere shortening, cytogenetic instability, and radiation sensitivity will compared in tissues and cells lacking telomerase in the presence or absence of functional WRN and BLM. Additionally, the role of WRN and BLM in cells that maintain their telomeres using recombination, rather than telomerase, will be explored. These studies should illuminate the function of WRN and BLM at human telomeres and improve understanding of the role of telomeres in natural human aging and cancer.
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