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A deletion within the murine Werner syndrome helicase induces sensitivity to inhibitors of topoisomerase and loss of cellular proliferative capacity.

http://www.ncbi.nlm.nih.gov/pubmed/9789047

Werner syndrome (WS) is an autosomal recessive disorder characterized by genomic instability and the premature onset of a number of age-related diseases. The gene responsible for WS encodes a member of the RecQ-like subfamily of DNA helicases. Here we show that its murine homologue maps to murine chromosome 8 in a region syntenic with the human WRN gene. We have deleted a segment of this gene and created Wrn-deficient embryonic stem (ES) cells and WS mice. While displaying reduced embryonic survival, live-born WS mice otherwise appear normal during their first year of life. Nonetheless, although several DNA repair systems are apparently intact in homozygous WS ES cells, such cells display a higher mutation rate and are significantly more sensitive to topoisomerase inhibitors (especially camptothecin) than are wild-type ES cells. Furthermore, mouse embryo fibroblasts derived from homozygous WS embryos show premature loss of proliferative capacity. At the molecular level, wild-type, but not mutant, WS protein copurifies through a series of centrifugation and chromatography steps with a multiprotein DNA replication complex.

Pubmed ID: 9789047 RIS Download

Mesh terms: Animals | Base Sequence | Camptothecin | Cell Division | Cells, Cultured | Chimera | Chromosome Mapping | Cloning, Molecular | Crosses, Genetic | DNA Helicases | DNA Primers | Female | Fetal Death | Homozygote | Humans | Male | Mice | Mice, Inbred C57BL | Mice, Inbred Strains | Mice, Knockout | Molecular Sequence Data | Muridae | Polymerase Chain Reaction | Polymorphism, Single-Stranded Conformational | Recombination, Genetic | Sequence Deletion | Stem Cells | Transfection | Werner Syndrome

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