The human disease Werner's Syndrome causes many symptoms resembling premature aging. The sequence of the gene defective in Werner's individuals encodes a DNA helicase. The yeast homolog of this gene, SGS1, is a DNA helicase concentrated in the yeast nucleolus. Mutations in this gene cause premature aging in yeast and the fragmentation of nucleolar rDNA into circles that accumulate to cause aging. In this grant we will investigate the molecular function of the Werner homolog SGS1 including study of how its loss leads to premature aging. The genesis of yeast rDNA circles will be investigated and the molecular mechanism of their accumulation and killing studied in detail. Finally, the generality of this aging mechanism in mammals will be investigated by screening for DNA circles in tissues of aging mice and humans. The overarching goal is to slow down aging in at least some organs to provide a higher quality of life as people enter their twilight years.
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