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Essential role of limiting telomeres in the pathogenesis of Werner syndrome

Nature Genetics volume 36, pages 877–882 (2004)Cite this article

Abstract

Mutational inactivation of the gene WRN causes Werner syndrome, an autosomal recessive disease characterized by premature aging, elevated genomic instability and increased cancer incidence1,2. The capacity of enforced telomerase expression to rescue premature senescence of cultured cells from individuals with Werner syndrome3 and the lack of a disease phenotype in Wrn-deficient mice with long telomeres4 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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Figure 1: Reduced lifespan and premature aging phenotypes in G4–G6 Terc−/− Wrn−/− mice.
Figure 2: Glucose intolerance and wound healing defects in G5 Terc−/− Wrn−/− mice.
Figure 3: Increased apoptosis and anaphase bridges in gastrointestinal crypts of G4–G6 Terc−/− Wrn−/− mice.
Figure 4: Accelerated telomere loss results in increased genomic instability and enhanced tumor predisposition in affected G4–G6 Terc−/− Wrn−/− mice.
Figure 5: Premature replicative senescence and increased DNA damage response in G4–G6 Terc−/− Wrn−/− cells.

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Acknowledgements

We thank P. Carpenter for the γH2AX and 53BP1 antibodies and K. K. Wong, R. Maser and members of the laboratory of S.C. for comments. S.C. is supported by a KO8 Mentored Award from the NIA and an Ellison New Scholar in Aging Award from the Ellison Medical Foundation. R.A.D. is an American Cancer Society Professor and a Steven and Michele Kirsch Investigator.

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Authors and Affiliations

  1. Department of Molecular Genetics, M.D. Anderson Cancer Center, Box 11, 1515 Holcombe Blvd., Houston, 77030, Texas, USA

    Sandy Chang, Asha S Multani, Noelia G Cabrera, Purnima Laud & Sen Pathak

  2. Department of Medical Oncology, Dana-Farber Cancer Institute,

    Maria L Naylor & Ronald A DePinho

  3. Departments of Medicine and Genetics, Harvard Medical School, 44 Binney Street (M413), Boston, 02115, Massachusetts, USA

    Maria L Naylor & Ronald A DePinho

  4. Department of Pathology, Brigham and Women's Hospital, Boston, 02115, Massachusetts, USA

    David Lombard

  5. Department of Biology, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Leonard Guarente

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  1. Sandy Chang
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Corresponding authors

Correspondence to Sandy Chang or Ronald A DePinho.

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Competing interests

L.G. is a founder, consultant and stockholder of Elixir Pharmaceuticals.

Supplementary information

Supplementary Fig. 1

a, Hypogonadism is present in 20-week old affected G4 mTerc−/− Wrn−/− animals. Spleen (top) and testis (bottom) were isolated from mice of the indicated genotypes. Scale bar: 2 mm.b, Quantitation of testicular mass of G0 mTERC+/− Wrn+/+, G0 mTERC+/− Wrn−/−, G4-6 mTERC−/− Wrn+/+ and affected G4-6 mTerc−/− Wrn−/− mice at 20 weeks of age. (PDF 24 kb)

Supplementary Fig. 2

Non-reciprocal translocations in bone marrow metaphases derived from affected G5 mTerc−/− Wrn/− mice at 22 weeks. Arrows point to red (chromosome 10) and blue (chromosome 12) translocations. (PDF 26 kb)

Supplementary Fig. 3

Chromosomal aberrations in passage 2 G5 mTerc−/− Wrn−/− MEF. Passage 2 MEFs isolated from embryos of the indicated genotypes were subject to Giemsa staining. Small arrows: fused chromosomes, large arrows: chromosome fragments, arrowheads: interstitial chromatid breaks. (PDF 42 kb)

Supplementary Table 1

Age-related changes in early generation telomerase-Werner compound mutant mice. (XLS 16 kb)

Supplementary Table 2

Characterization of chromosomal aberrations and telomere lengths in telomerase-Werner compound mutant mice and MEFs. (XLS 17 kb)

Supplementary Table 3

Cancer incidence in telomerase-Werner compound mutant mice. (XLS 9 kb)

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Chang, S., Multani, A., Cabrera, N. et al. Essential role of limiting telomeres in the pathogenesis of Werner syndrome. Nat Genet 36, 877–882 (2004). https://doi.org/10.1038/ng1389

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