Genomic instability in laminopathy-based premature aging

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journal

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Author(s)

  • Baohua Liu
  • Jianming Wang
  • 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

Detail(s)

Original languageEnglish
Pages (from-to)780-785
Journal / PublicationNature Medicine
Volume11
Issue number7
Publication statusPublished - Jul 2005
Externally publishedYes

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.

Citation Format(s)

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

In: Nature Medicine, Vol. 11, No. 7, 07.2005, p. 780-785.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journal