The DNA helicase activity of yeast Sgs1p is essential for normal lifespan but not for resistance to topoisomerase inhibitors

The Saccharomyces cerevisiae SGS1 gene is a member of the RecQ family of AT P-dependent DNA helicases, which includes the human WRN, BLM and RECQ4 gene s. Mutations in the WRN gene cause the human premature ageing disorder, Wer ner's syndrome. Deletion of the SGS1 gene also causes premature ageing in y east, suggesting that the molecular mechanisms of cellular ageing may be ev olutionarily conserved. To investigate the role of the RecQ helicase domain in ageing, a point mutation (SGS1 K-706-->A) known to eliminate the DNA he licase activity of Sgs1p was constructed. This mutant allele failed to resc ue the premature ageing of the sgs1 Delta strain, demonstrating that Sgs1p DNA helicase activity is required for a normal lifespan. In contrast, the S GS1 K-706-->A allele was sufficient to rescue the hypersensitivity of the s gs1 Delta strain to topoisomerase inhibitors, but not other genotoxic agent s. These findings support the idea that Sgs1p fulfils multiple cellular fun ctions, and that DNA helicase activity is dispensable for some of these (e. g. functional interaction with topoisomerases), but essential for others (e .g. longevity). (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.