TY - JOUR
T1 - Mutations in the WRN gene in mice accelerate mortality in a p53-null background
AU - Lombard, David B.
AU - Beard, Caroline
AU - Johnson, Brad
AU - Marciniak, Robert A.
AU - Dausman, Jessie
AU - Bronson, Roderick
AU - Buhlmann, Janet E.
AU - Lipman, Ruth
AU - Curry, Ruth
AU - Sharpe, Arlene
AU - Jaenisch, Rudolf
AU - Guarente, Leonard
PY - 2000/5
Y1 - 2000/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=17544402913&partnerID=8YFLogxK
U2 - 10.1128/MCB.20.9.3286-3291.2000
DO - 10.1128/MCB.20.9.3286-3291.2000
M3 - Article
C2 - 10757812
AN - SCOPUS:17544402913
SN - 0270-7306
VL - 20
SP - 3286
EP - 3291
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
IS - 9
ER -