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Letter
Nature Medicine  11, 780 - 785 (2005)
Published online: 26 June 2005; | doi:10.1038/nm1266

Genomic instability in laminopathy-based premature aging

Baohua Liu1, Jianming Wang2, Kui Ming Chan1, Wai Mui Tjia3, Wen Deng4, Xinyuan Guan3, Jian-dong Huang1, Kai Man Li1, Pui Yin Chau1, David J Chen5, Duanqing Pei6, Alberto M Pendas7, Juan Cadiñanos7, Carlos López-Otín7, Hung Fat Tse8, Chris Hutchison9, Junjie Chen10, Yihai Cao11, Kathryn S E Cheah1, Karl Tryggvason12 & Zhongjun Zhou1

1  Department of Biochemistry, University of Hong Kong, 21 Sassoon Road, Hong Kong.

2  Department of Molecular Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.

3  Department of Clinical Oncology, University of Hong Kong, 21 Sassoon Road, Hong Kong.

4  Department of Anatomy, University of Hong Kong, 21 Sassoon Road, Hong Kong.

5  Department of Radiation Oncology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.

6  Department of Pharmacology, University of Minnesota, 101 Pleasant Street SE, Minneapolis, Minnesota 55455, USA.

7  Departamento de Bioquimica y Biologia Molecular, Instituto Universitario de Oncologia, Universidad de Oviedo, 33006-Oviedo, Spain.

8  Department of Medicine, University of Hong Kong, 21 Sassoon Road, Hong Kong.

9  Department of Biological and Biomedical Sciences, University of Durham, Durham, DH1 3HP, UK.

10  Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA.

11  Microbiology and Tumor Center, Karolinska Institute, Scheeles vag 2, Stockholm, S-171 77, Sweden.

12  Medical Biochemistry and Biophysics, Karolinska Institute, Scheeles vag 2, Stockholm, S-171 77, Sweden.

Correspondence should be addressed to Zhongjun Zhou zhongjun@hkucc.hku.hk
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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ISSN: 1078-8956
EISSN: 1546-170X
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