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.Werner's Syndrome (WS) is a recessive genetic disease which shows premature onset of many pathologies normally associated with old age (18). Patients with WS appear normal during the first decade of life. The first manifestation of this disease is typically growth failure during adolescence. Subsequently, these patients suffer prematurely from a variety of age-related disorders: skin changes, osteoporosis, diabetes, accelerated atherosclerosis, and cancer, particularly sarcomas. Fibroblasts derived from individuals with WS divide many fewer times prior to senescence than do fibroblasts from agematched control individuals (13). Genomic instability has been observed in WS cells, as chromosomal rearrangements (5,19,21) and as mutations within the hypoxanthine phosphoribosyltransferase gene (HPRT); in vivo, an increased frequency of HPRT mutant cells has been observed in patients with WS (2,3,14). The gene defective in WS, WRN, encodes a protein of 1,432 amino acids with similarity to the RecQ subfamily of DNA helicases (26). Although mutations throughout the WRN gene have been observed in the homozygous state, homozygosity for a mutation very near the 3Ј end of the WRN open reading frame is sufficient to lead to the disease (15).A mouse knockout (KO) of the WRN gene has been described (10). Lebel and Leder deleted exons III and IV in the catalytic helicase domain of the WRN locus, a mutation predicted to eliminate catalytic function. Cells containing this mutation express an internally deleted, nearly full-length WRN protein. Homozygous mutant mice are viable, indicating that this particular mutation is not lethal. However Lebel and Leder showed a decreased embryonic survival of their mutant: on a C57BL/6-129/SvEv outbred background and on a 129/ SvEv inbred background, the ratios of ϩ/ϩ:ϩ/Ϫ:Ϫ/Ϫ mice born are 1:2.0:0.8 and 1:1.9:0.6, respectively. Mutant embryonic stem (ES) cells have an approximately sixfold increased mutation rate at the HPRT locus. They are also 10-fold more sensitive to camptothecin, a topoisomerase I inhibitor, and are two-to threefold more sensitive to etoposide, a topoisomerase II inhibitor. Late-passage mutant embryonic fibro...
RI, the El revertant RI; R2, the El revertant R2; +, the New Jersey wild type; R5, the El revertant R5; R6, the El revertant R6; +, the New Jersey wild type; El, the ts mutant El. The identification of the structural proteins is given on the right. The designations are from top to bottom: L, the large protein required for transcription (molecular weight, 190,000); G, the surface glycoprotein (molecular weight, 70,000); NS, the phosphorylated protein required for transcription; N, the structural protein of the ribonucleoprotein core (molecular weight, 50,000); X, a minor phosphorylated component; and M, the matrix protein (molecular weight, 30,000).
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