Genomic instability in laminopathy-based premature aging. Export

@article{citeulike:239621, 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.}, address = {Department of Biochemistry, University of Hong Kong, 21 Sassoon Road, Hong Kong.}, author = {Liu, Baohua and Wang, Jianming and Chan, Kui Ming M. and Tjia, Wai Mui M. and Deng, Wen and Guan, Xinyuan and Huang, Jian-Dong D. and Li, Kai Man M. and Chau, Pui Yin Y. and Chen, David J J. and Pei, Duanqing and Pendas, Alberto M M. and Cadi\~{n}anos, Juan and L\'{o}pez-Ot\'{\i}n, Carlos and Tse, Hung Fat F. and Hutchison, Chris and Chen, Junjie and Cao, Yihai and Cheah, Kathryn S E S. and Tryggvason, Karl and Zhou, Zhongjun}, citeulike-article-id = {239621}, citeulike-linkout-0 = {http://dx.doi.org/10.1038/nm1266}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/15980864}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=15980864}, day = {26}, doi = {10.1038/nm1266}, issn = {1078-8956}, journal = {Nat Med}, month = {June}, posted-at = {2005-06-28 21:08:32}, priority = {4}, title = {Genomic instability in laminopathy-based premature aging.}, url = {http://dx.doi.org/10.1038/nm1266}, year = {2005} }

TY - JOUR ID - citeulike:239621 L3 - citeulike-article-id:239621 N2 - 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. JF - Nat Med SN - 1078-8956 AD - Department of Biochemistry, University of Hong Kong, 21 Sassoon Road, Hong Kong. TI - Genomic instability in laminopathy-based premature aging. AU - Liu, Baohua AU - Wang, Jianming AU - Chan, Kui Ming AU - Tjia, Wai Mui AU - Deng, Wen AU - Guan, Xinyuan AU - Huang, Jian-Dong AU - Li, Kai Man AU - Chau, Pui Yin AU - Chen, David J AU - Pei, Duanqing AU - Pendas, Alberto M AU - Cadiñanos, Juan AU - López-Otín, Carlos AU - Tse, Hung Fat AU - Hutchison, Chris AU - Chen, Junjie AU - Cao, Yihai AU - Cheah, Kathryn S E AU - Tryggvason, Karl AU - Zhou, Zhongjun PY - 2005/06/26/ UR - http://dx.doi.org/10.1038/nm1266 ER -