Mutations in the WRN gene in mice accelerate mortality in a p53-null background

Werner's syndrome (WS) is a human disease with manifestations resembling pr emature aging, The gene defective in TVS, WRN, encodes a DNA helicase, Here , we describe the generation of mice bearing a mutation that eliminates exp ression of the C terminus of the helicase domain of the WRN protein. Mutant mice are born at the expected Mendelian frequency and do not show any over t histological signs of accelerated senescence. These mice are capable of l iving beyond 2 years of age. Cells from these animals do not show elevated susceptibility to the genotoxins camptothecin or 4-NQO. However, mutant fib roblasts senesce approximately one passage earlier than controls, Important ly, WRN-/-;p53(-/-) mice show an increased mortality rate relative to WRN+/ -;p53(-/-) animals. We consider possible models for the synergy. between p5 3 and WRN mutations for the determination of life span.