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 Tryggvason; Zhongjun Zhou

doi:10.1038/nm1266

Genomic instability in laminopathy-based premature aging

Nat Med. 2005 Jul;11(7):780-5. doi: 10.1038/nm1266. Epub 2005 Jun 26.

Affiliation

¹ Department of Biochemistry, University of Hong Kong, 21 Sassoon Road, Hong Kong.

PMID: 15980864
DOI: 10.1038/nm1266

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aging, Premature / genetics*
Animals
Bone Marrow Cells / physiology
Bone Marrow Cells / radiation effects
Cellular Senescence / genetics
Chromosomal Proteins, Non-Histone
Chromosome Aberrations
DNA / genetics
DNA Damage / genetics*
DNA Repair / physiology*
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Fibroblasts / pathology
Fibroblasts / radiation effects
Gamma Rays
Genomic Instability*
Histones / genetics
Histones / metabolism
Histones / radiation effects
Humans
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism
Lamin Type A / genetics*
Lamin Type A / metabolism
Membrane Proteins / genetics*
Membrane Proteins / metabolism
Metalloendopeptidases / genetics*
Metalloendopeptidases / metabolism
Mice
Mice, Mutant Strains
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Phosphoproteins / genetics
Phosphoproteins / metabolism
Protein Precursors / genetics
Protein Precursors / metabolism
Rad51 Recombinase
Tumor Suppressor p53-Binding Protein 1

Substances

Chromosomal Proteins, Non-Histone
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
Tumor Suppressor p53-Binding Protein 1
prelamin A
DNA
RAD51 protein, human
Rad51 Recombinase
Rad51 protein, mouse
Metalloendopeptidases
Zmpste24 protein, mouse