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 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.
Lombard
D B
DB
Department of Biology, Massachusetts Institute of Technology, Boston, Massachusetts, USA.
Beard
C
C
Johnson
B
B
Marciniak
R A
RA
Dausman
J
J
Bronson
R
R
Buhlmann
J E
JE
Lipman
R
R
Curry
R
R
Sharpe
A
A
Jaenisch
R
R
Guarente
L
L
D015112:4-Nitroquinoline-1-oxide / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002166:Camptothecin / Q000378:metabolism; D002455:Cell Division; D002478:Cells, Cultured; D016922:Cellular Senescence; D003001:Cloning, Molecular; D004265:DNA Helicases / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000378:metabolism; D005090:Exodeoxyribonucleases; D005347:Fibroblasts / Q000378:metabolism; D015723:Gene Library; D008017:Life Expectancy; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D015363:Quinolones / Q000378:metabolism; D053484:RecQ Helicases; D013154:Spleen / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D000071657:Werner Syndrome Helicase
C120195:4-nitroquinolone-1-oxide; D015363:Quinolones; D016159:Tumor Suppressor Protein p53; D015112:4-Nitroquinoline-1-oxide; D005090:Exodeoxyribonucleases; D004265:DNA Helicases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase; D002166:Camptothecin