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Letter
Nature Medicine 11, 780 - 785 (2005)
Published online: 26 June 2005 | Corrected online: 25 July 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
Abstract
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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