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Genomic instability in laminopathy-based premature aging
- Source :
- Nature Medicine. 11:780-785
- Publication Year :
- 2005
- Publisher :
- Springer Science and Business Media LLC, 2005.
-
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.
- Subjects :
- Premature aging
Genome instability
congenital, hereditary, and neonatal diseases and abnormalities
DNA Repair
Chromosomal Proteins, Non-Histone
DNA repair
DNA damage
Bone Marrow Cells
Laminopathy
Biology
Genomic Instability
General Biochemistry, Genetics and Molecular Biology
Progeroid syndromes
Histones
Mice
medicine
Animals
Humans
Protein Precursors
Cellular Senescence
Chromosome Aberrations
Genetics
integumentary system
Intracellular Signaling Peptides and Proteins
Membrane Proteins
Metalloendopeptidases
Nuclear Proteins
Aging, Premature
DNA
General Medicine
Fibroblasts
Lamin Type A
Phosphoproteins
medicine.disease
Progerin
Mice, Mutant Strains
Cell biology
DNA-Binding Proteins
Gamma Rays
Rad51 Recombinase
Tumor Suppressor p53-Binding Protein 1
Lamin
DNA Damage
Subjects
Details
- ISSN :
- 1546170X and 10788956
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Nature Medicine
- Accession number :
- edsair.doi.dedup.....fd11141cb7e15e7d786d6071706e95a4