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Molecular and Cellular Biology, May 2000, p. 3286-3291, Vol. 20, No. 9
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Mutations in the WRN Gene in Mice Accelerate Mortality in a p53-Null Background

David B. Lombard,1 Caroline Beard,2 Brad Johnson,1 Robert A. Marciniak,1 Jessie Dausman,2 Roderick Bronson,3 Janet E. Buhlmann,4 Ruth Lipman,3 Ruth Curry,2 Arlene Sharpe,4 Rudolf Jaenisch,3 and Leonard Guarente1,*

Department of Biology, Massachusetts Institute of Technology,1 and Whitehead Institute,2 Cambridge, and School of Veterinary Medicine, Tufts University,3 and Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston,4 Massachusetts

Received 7 December 1999/Accepted 31 January 2000

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.

* Corresponding author. Mailing address: Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, MA 02139-4307. Phone: (617) 253-6965. Fax: (617) 253-8699. E-mail: leng{at}mit.edu.

Molecular and Cellular Biology, May 2000, p. 3286-3291, Vol. 20, No. 9
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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