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Cited by 462Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsNuclear Structure and Function

Essential role of limiting telomeres in the pathogenesis of Werner syndrome

Chang, Sandy, Multani, Asha S, Cabrera, Noelia G, Naylor, Maria L, Laud, Purnima, Lombard, David, Pathak, Sen, Guarente, Leonard +1 more·2004·Nature Genetics
DOI 10.1038/ng1389
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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.

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Crossref · 10.1038/ng1389

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  • The absence of disease in mouse models of Werner and Ataxia-Telangiectasia syndromes has been linked to species differences in telomere length, because crossing these models with telomerase-deficient mice made the disease apparent.

    “In support of this hypothesis, lack of a disease phenotype in mouse models of other human diseases, such as Werner and Ataxia-Telangiectasia syndromes, has been linked to species-specific differences in telomere length, as when these models were crossed with mice lacking telomerase activity, the disease became apparent (Chang et al., 2004; Wong et al., 2003).”

    From Short Telomeres and Stem Cell Exhaustion Model Duchenne Muscular Dystrophy in mdx/mTR Mice (2010) · cites this paper as Chang et al., 2004

  • Signal-free ends represent chromosome ends with the shortest telomeres and correlate with increased chromosome fusions and tissue dysfunction in telomerase knockout mice.

    “SFEs represent chromosome ends with the shortest telomeres and correlate with and increased incidence of chromosome fusions and tissue dysfunction in vivo in telomerase knockout mice (Chang et al., 2004).”

    From Short Telomeres and Stem Cell Exhaustion Model Duchenne Muscular Dystrophy in mdx/mTR Mice (2010) · cites this paper as Chang et al., 2004

  • In WRN/Terc double deficient animals, phenotypes reminiscent of human WS that are not observed in either single mutant are present: osteopenia, diabetes, and sarcomas.

    “In the WRN/Terc double deficient animals, phenotypes reminiscent of human WS that are not observed in either single mutant are present: osteopenia, diabetes, and sarcomas.”

    From DNA Repair, Genome Stability, and Aging (2005) · cites this paper as Chang et al., 2004

  • The hypothesis that WRN-deficient mice may not demonstrate a strong phenotype due to abundant mouse telomere reserve has been proven correct by generation of mice deficient in both WRN and Terc.

    “This hypothesis has been proven correct by the generation of mice deficient in both WRN and Terc (Chang et al., 2004; Du et al., 2004”

    From DNA Repair, Genome Stability, and Aging (2005) · cites this paper as Chang et al., 2004

  • The lack of downstream cellular defects in mouse cells is consistent with the large functional reserve of mouse telomeres.

    “Inactivation of SIRT6 leads to H3K9 hyperacetylation at telomeric chromatin in both human and mouse cells, but the mouse cells do not display the downstream cellular defects observed in human cells, which is consistent with the large functional reserve of mouse telomeres (Supplementary Fig. 13d; data not shown)14,25.”

    From SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin (2008) · cites this paper as [25]

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Authors
Chang, S., Multani, A. S., Cabrera, N. G., Naylor, M. L., Laud, P., Lombard, D., Pathak, S., Guarente, L., & DePinho, R. A.
Affiliations
  • The University of Texas MD Anderson Cancer Center (US)
  • Harvard University (US)
  • Brigham and Women's Hospital (US)
  • Massachusetts Institute of Technology (US)
Corresponding author
  • Chang, Sandy
  • DePinho, Ronald A
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2004-07-04
Volume
36
Issue
8
Pages
877-882
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng1389
OpenAlex
W2050228381
Cited by
462
References
24
Citations by year
2026: 4 · 2025: 8 · 2024: 12 · 2023: 15 · 2022: 12 · 2021: 19 · 2020: 10 · 2019: 25 · 2018: 16 · 2017: 11 · 2016: 21 · 2015: 14 · 2014: 17 · 2013: 18 · 2012: 21
FWCI
25.35
Type
journal article
Language
en
Open access
closed
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Cancer Society
  • Ellison Medical Foundation
  • National Institute on Aging (K08AG024873, K08AG001019)
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
Keywords
Werner syndrome, WRN gene, telomere shortening, telomerase, TERC, premature aging, replicative senescence, genomic instability, chromosomal instability, cancer susceptibility, telomere dysfunction, DNA damage foci
MeSH terms
Animals, Cells, Cultured, Diabetes Mellitus, Type 2, DNA Damage, Female, Life Expectancy, Mice, Mutant Strains, Neoplasms, Experimental, Werner Syndrome, Wound Healing, Telomere, Cellular Senescence, Apoptosis, Aging, Premature, Chromosomal Instability, Mice

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