Genomic instability in laminopathy-based premature aging

Baohua Liu, Jianming Wang, Kui Ming Chan, Wai Mui Tjia, Wen Deng, Xinyuan Guan, Jian Dong Huang, Kai Man Li, Pui Yin Chau, David J. Chen, Duanqing Pei, Alberto M. Pendas, Juan Cadiñanos, Carlos López-Otín, Hung Fat Tse, Chris Hutchison, Junjie Chen, Yihai Cao, Kathryn S E Cheah, Karl TryggvasonZhongjun Zhou

Research output: Contribution to journalArticle

434 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)780-785
Number of pages6
JournalNature medicine
Volume11
Issue number7
DOIs
StatePublished - Jul 1 2005

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Liu, B., Wang, J., Chan, K. M., Tjia, W. M., Deng, W., Guan, X., Huang, J. D., Li, K. M., Chau, P. Y., Chen, D. J., Pei, D., Pendas, A. M., Cadiñanos, J., López-Otín, C., Tse, H. F., Hutchison, C., Chen, J., Cao, Y., Cheah, K. S. E., ... Zhou, Z. (2005). Genomic instability in laminopathy-based premature aging. Nature medicine, 11(7), 780-785. https://doi.org/10.1038/nm1266