Author: ["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 Tryggvason","Zhongjun Zhou"]
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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.Cite this article
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 