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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NOTE: In the version of this article initially published online, Supplementary Figure 1 was incorrect. The error has been corrected online.
Busuttil, R.A., Dolle, M., Campisi, J. & Vijga, J. Genomic instability, aging, and cellular senescence. Ann. N. Y. Acad. Sci. 1019, 245–255 (2004).
Hasty, P., Campisi, J., Hoeijmakers, J., van Steeg, H. & Vijg, J. Aging and genome maintenance: lessons from the mouse? Science 299, 1355–1359 (2003).
Karanjawala, Z.E. & Lieber, M.R. DNA damage and aging. Mech. Ageing Dev. 125, 405–416 (2004)
Eriksson, M. et al. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423, 293–298 (2003).
De Sandre-Giovannoli, A. et al. Lamin a truncation in Hutchinson-Gilford progeria. Science 300, 2055 (2003)
Hutchison, C.J. Lamins: building blocks or regulators of gene expression? Nat. Rev. Mol. Cell Biol. 3, 848–858 (2002).
Mounkes, L.C., Kozlov, S., Hernandez, L., Sullivan, T. & Stewart, C.L. A progeroid syndrome in mice is caused by defects in A-type lamins. Nature 423, 298–301 (2003).
Pendas, A.M. et al. Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase-deficient mice. Nat. Genet. 31, 94–99 (2002).
Bergo, M.O. et al. Zmpste24 deficiency in mice causes spontaneous bone fractures, muscle weakness, and a prelamin A processing defect. Proc. Natl. Acad. Sci. USA 99, 13049–13054 (2002)
Agarwal, A.K., Fryns, J.P., Auchus, R.J. & Garg, A. Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia. Hum. Molec. Genet. 12, 1995–2001 (2003).
Luzi, P. et al. Ploidy pattern and cell cycle in breast cancer as detected by image analysis and flow cytometry. Cytometry 18, 79–87 (1994).
Rajagopalan, H. et al. Inactivation of hCDC4 can cause chromosomal instability. Nature 428, 77–81 (2004).
Mukherjee, A.B. & Costello, C. Aneuploidy analysis in fibroblasts of human premature aging syndromes by FISH during in vitro cellular aging. Mech. Ageing Dev. 103, 209–222 (1998).
d'Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003).
Sedelnikova, O.A., et al. Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks. Nat. Cell Biol. 6, 168–170 (2004).
Seluanov, A., Mittelman, D., Pereira-Smith, O.M., Wilson, J.H. & Gorbunova, V. DNA end joining becomes less efficient and more error-prone during cellular senescence. Proc. Natl. Acad. Sci. USA 101, 7624–7629 (2004).
Chan, D.W. et al. Autophosphorylation of the DNA-dependent protein kinase catalytic subunit is required for rejoining of DNA double-strand breaks. Genes Dev. 16, 2333–2338 (2002).
Li, X.T., et al. Identification of factors influencing strand bias in oligonucleotide-mediated recombination in Escherichia coli. Nucleic Acids Res. 31, 6674–6687 (2003).
Navarro, C.L. et al. Loss of ZMPSTE24 (FACE-1) causes autosomal recessive restrictive dermopathy and accumulation of lamin A precursors. Hum. Mol. Genet. 14, 1503–1513 (2005).
Taylor, T.J. & Knipe, D.M. Proteomics of herpes simplex virus replication compartments: association of cellular DNA replication, repair, recombination, and chromatin remodeling proteins with ICP8. J. Virol. 78, 5856–5866 (2004).
Goldman, A.E., Moir, R.D., Montag-Lowy, M., Stewart, M. & Goldman, R.D. Pathway of incorporation of microinjected lamin A into the nuclear envelope. J. Cell Biol. 119, 725–735 (1992).
Goldman, R.D., et al. Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome. Proc. Natl. Acad. Sci. USA 15, 8963–8968 (2004).
Burma, S. et al. DNA-dependent protein kinase-independent activation of p53 in response to DNA damage. J. Biol. Chem. 274, 17139–17143 (1999).
Ward, I.M. et al. 53BP1 is required for class switch recombination. J. Cell Biol. 165, 459–464 (2004).
Lou, Z., Chini, C.C., Minter-Dykhouse, K. & Chen, J. Mediator of DNA damage checkpoint protein 1 regulates BRCA1 localization and phosphorylation in DNA damage checkpoint control. J. Biol. Chem. 278, 13599–13602 (2003).
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.
The authors declare no competing financial interests.
Sustained 53BP1 foci at sites of DNA lesions in camptothecin-treated cells. (PDF 2175 kb)
Zmpste24 cDNA rescues the defective recruitment of 53BP1 and Rad51 in Zmpste24−/− MEFs. (PDF 201 kb)
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). https://doi.org/10.1038/nm1266
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