Essential role of limiting telomeres in the pathogenesis of Werner syndrome

Abstract

Mutational inactivation of the gene WRN causes Werner syndrome, an autosomal recessive disease characterized by premature aging, elevated genomic instability and increased cancer incidence. The capacity of enforced telomerase expression to rescue premature senescence of cultured cells from individuals with Werner syndrome and the lack of a disease phenotype in Wrn-deficient mice with long telomeres implicate telomere attrition in the pathogenesis of Werner syndrome. Here, we show that the varied and complex cellular phenotypes of Werner syndrome are precipitated by exhaustion of telomere reserves in mice. In late-generation mice null with respect to both Wrn and Terc (encoding the telomerase RNA component), telomere dysfunction elicits a classical Werner-like premature aging syndrome typified by premature death, hair graying, alopecia, osteoporosis, type II diabetes and cataracts. This mouse model also showed accelerated replicative senescence and accumulation of DNA-damage foci in cultured cells, as well as increased chromosomal instability and cancer, particularly nonepithelial malignancies typical of Werner syndrome. These genetic data indicate that the delayed manifestation of the complex pleiotropic of Wrn deficiency relates to telomere shortening.

Cell intrinsic and extrinsic mechanisms of stem cell aging depend on telomere status

“…In line with this assumption, Wrn knockout mice with long telomere reserves did not display typical cellular or clinical phenotypes of human Werner syndrome (Lombard et al, 2000). However, in late generation Terc -/-mice, deletion of Wrn accelerated the overall attrition of telomere length, resulting in phenotypes resembling human Werner syndrome, including early onset of age-related disorders, increased incidence of mesenchymal cancers, and premature death (Chang et al, 2004;Du et al, 2004). (iii) p53: p53 appears to have a more complicated role in stem cell aging.…”

Cancer and aging: the importance of telomeres in genome maintenance

“…Alternatively, or in addition, the repair proteins, in concert with the telomere-associated proteins with which they interact, may suppress the inappropriate fusion or recombination of telomeres. In support of this possibility, mammalian cells deficient in Ku, components of the RMN complex, or WRN all show an increase in telomere erosion, fusions or other signs of dysfunction [80,[97][98][99].…”

Accelerated ageing: from mechanism to therapy through animal models

“…A Wrn-knockout mouse model recapitulates the alterations observed in WS patients at the molecular and cellular levels but, strikingly, Wrn deficiency does not causes an accelerated ageing phenotype in mice (Lombard et al 2000). In contrast, progeroid symptoms closely recapitulating WS develop in double-mutant mice lacking both Wrn and telomerase activity, revealing the critical role of Wrn in telomere biology and its relevance for the progeroid phenotypes caused by WRN deficiency (Chang et al 2004;Multani and Chang 2007). These findings indicate that mice and humans may show different sensitivity to progeroidcausing alterations, and these differences have to be carefully taken in consideration to interpret results derived from the use of murine models.…”