Open AccessMutations in the WRN Gene in Mice Accelerate Mortality in a p53-Null Background
Author(s) -
David B. Lombard,
Caroline Beard,
Brad Johnson,
Robert A. Marciniak,
Jessie Dausman,
Roderick T. Bronson,
Janet E. Buhlmann,
Ruth D. Lipman,
Ruth Curry,
Arlene H. Sharpe,
Rudolf Jaenisch,
Leonard Guarente
Publication year - 2000
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.20.9.3286-3291.2000
Subject(s) - werner syndrome , biology , helicase , premature aging , mutant , gene , mutation , genetics , dna repair , telomere , microbiology and biotechnology , rna
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 toWRN+/− ;p53−/− animals. We consider possible models for the synergy betweenp53 andWRN mutations for the determination of life span.