| 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. |
| Authors | 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
(Affiliation: Department of Biochemistry, University of Hong Kong, 21 Sassoon Road, Hong Kong.)
|
| Journal | Nature medicine
(Nat Med)
Vol. 11
Issue 7
Pg. 780-5
(Jul 2005)
ISSN: 1078-8956 United States |
| PMID | 15980864
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- DNA-Binding Proteins
- H2AX protein, mouse
- Histones
- Intracellular Signaling Peptides and Proteins
- Lamin Type A
- Membrane Proteins
- Nuclear Proteins
- Phosphoproteins
- Protein Precursors
- TP53BP1 protein, human
- Trp53bp1 protein, mouse
- prelamin A
- DNA
- RAD51 protein, human
- Rad51 Recombinase
- Rad51 protein, mouse
- Metalloendopeptidases
- Zmpste24 protein, mouse
|
| Topics |
- Aging, Premature
(genetics)
- Animals
- Bone Marrow Cells
(physiology, radiation effects)
- Cell Aging
(genetics)
- Chromosome Aberrations
- DNA
(genetics)
- DNA Damage
(genetics)
- DNA Repair
(physiology)
- DNA-Binding Proteins
(genetics, metabolism)
- Fibroblasts
(pathology, radiation effects)
- Gamma Rays
- Genomic Instability
- Histones
(genetics, metabolism, radiation effects)
- Humans
- Intracellular Signaling Peptides and Proteins
(genetics, metabolism)
- Lamin Type A
(genetics, metabolism)
- Membrane Proteins
(genetics, metabolism)
- Metalloendopeptidases
(genetics, metabolism)
- Mice
- Mice, Mutant Strains
- Nuclear Proteins
(genetics, metabolism)
- Phosphoproteins
(genetics, metabolism)
- Protein Precursors
(genetics, metabolism)
- Rad51 Recombinase
|
