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Genomic instability in laminopathy-based premature aging

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Premature aging syndromes often result from mutations in nuclear proteins involved in the maintenance of genomic integrity. Lamin A is a major component of the nuclear lamina and nuclear skeleton. Truncation in lamin A causes Hutchinson-Gilford progerial syndrome (HGPS), a severe form of early-onset premature aging. Lack of functional Zmpste24, a metalloproteinase responsible for the maturation of prelamin A, also results in progeroid phenotypes in mice and humans. We found that Zmpste24-deficient mouse embryonic fibroblasts (MEFs) show increased DNA damage and chromosome aberrations and are more sensitive to DNA-damaging agents. Bone marrow cells isolated from Zmpste24−/− mice show increased aneuploidy and the mice are more sensitive to DNA-damaging agents. Recruitment of p53 binding protein 1 (53BP1) and Rad51 to sites of DNA lesion is impaired in Zmpste24−/− MEFs and in HGPS fibroblasts, resulting in delayed checkpoint response and defective DNA repair. Wild-type MEFs ectopically expressing unprocessible prelamin A show similar defects in checkpoint response and DNA repair. Our results indicate that unprocessed prelamin A and truncated lamin A act dominant negatively to perturb DNA damage response and repair, resulting in genomic instability which might contribute to laminopathy-based premature aging.

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Figure 1: Early replicative arrest and genomic instability in Zmpste24−/− MEFs.
Figure 2: DNA damage and sensitivity to DNA damage treatments.
Figure 3: Delayed recruitment of 53BP1 to sites of DNA lesions in irradiated cells.
Figure 4: Defective DNA repair.

Change history

  • 25 July 2005

    In the version of this article initially published online, Supplementary Figure 1 was incorrect. The error has been corrected online.


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    NOTE: In the version of this article initially published online, Supplementary Figure 1 was incorrect. The error has been corrected online.


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This work was supported by a Seed Fund for Basic Research from University of Hong Kong. (Z. Z.), Research Grants Council (Hong Kong) Central Allocation Vote, University Grants Committee (Hong Kong) Area of Excellence Developmental Genomics and Skeletal Research. J. W. is a Postdoctoral Fellow of the American Heart Association. Y. C. and K. T. are supported by the Swedish Cancer Foundation and the Swedish Research Council. C. L.-O. is supported by grants from Ministerio de Ciencia y Tecnología-Spain, Fundación La Caixa and European Union (FP5, FP6 Cancer Degradome). The Instituto Universitario de Oncología is supported by Obra Social Cajastur-Asturias and Red de Centros de Cáncer-Instituto Carlos III, Spain. We thank D. Jin for discussions, J. Marsh for proofreading the manuscript, W.-S. O for help with comet assay, A. Lui for flow cytometry analysis, W. Y. Wong for animal husbandry, T. Arooz for help with irradiation experiments, M. Jasin for pDR-GFP and pCBA-I-SceI plasmid and V. Gorbunova for the GFP-Pem1-Ad2 plasmid.

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Correspondence to Zhongjun Zhou.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Sustained 53BP1 foci at sites of DNA lesions in camptothecin-treated cells. (PDF 2175 kb)

Supplementary Fig. 2

Zmpste24 cDNA rescues the defective recruitment of 53BP1 and Rad51 in Zmpste24−/− MEFs. (PDF 201 kb)

Supplementary Fig. 3

Ectopic expression of unprocessed prelamin A confers wild-type MEFs with genomic instability. (PDF 107 kb)

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Liu, B., Wang, J., Chan, K. et al. Genomic instability in laminopathy-based premature aging. Nat Med 11, 780–785 (2005).

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