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

David B. Lombard, Caroline Beard, Brad Johnson, Robert A. Marciniak, Jessie Dausman, Roderick Bronson, Janet E. Buhlmann, Ruth Lipman, Ruth Curry, Arlene Sharpe, Rudolf Jaenisch, Leonard Guarente

Research output: Contribution to journalArticlepeer-review

162 Scopus citations


Werner's syndrome (WS) is a human disease with manifestations resembling premature aging. The gene defective in WS, WRN, encodes a DNA helicase. Here, we describe the generation of mice bearing a mutation that eliminates expression 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 overt histological signs of accelerated senescence. These mice are capable of living beyond 2 years of age. Cells from these animals do not show elevated susceptibility to the genotoxins camptothecin or 4-NQO. However, mutant fibroblasts senesce approximately one passage earlier than controls. Importantly, WRN(-/-);p53(-/-) mice show an increased mortality rate relative to WRN(+/-);p53(-/-) animals. We consider possible models for the synergy between p53 and WRN mutations for the determination of life span.

Original languageEnglish
Pages (from-to)3286-3291
Number of pages6
JournalMolecular and Cellular Biology
Issue number9
StatePublished - May 2000
Externally publishedYes


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