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
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Research Support, Non-U.S. Gov't
MeSH terms
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Aging, Premature / genetics*
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Animals
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Bone Marrow Cells / physiology
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Bone Marrow Cells / radiation effects
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Cellular Senescence / genetics
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Chromosomal Proteins, Non-Histone
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Chromosome Aberrations
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DNA / genetics
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DNA Damage / genetics*
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DNA Repair / physiology*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Fibroblasts / pathology
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Fibroblasts / radiation effects
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Gamma Rays
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Genomic Instability*
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Histones / genetics
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Histones / metabolism
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Histones / radiation effects
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Lamin Type A / genetics*
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Lamin Type A / metabolism
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Membrane Proteins / genetics*
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Membrane Proteins / metabolism
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Metalloendopeptidases / genetics*
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Metalloendopeptidases / metabolism
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Mice
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Mice, Mutant Strains
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Protein Precursors / genetics
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Protein Precursors / metabolism
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Rad51 Recombinase
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Tumor Suppressor p53-Binding Protein 1
Substances
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Chromosomal Proteins, Non-Histone
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DNA-Binding Proteins
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H2AX protein, mouse
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Histones
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Intracellular Signaling Peptides and Proteins
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Lamin Type A
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Membrane Proteins
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Nuclear Proteins
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Phosphoproteins
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Protein Precursors
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TP53BP1 protein, human
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Trp53bp1 protein, mouse
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Tumor Suppressor p53-Binding Protein 1
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prelamin A
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DNA
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RAD51 protein, human
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Rad51 Recombinase
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Rad51 protein, mouse
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Metalloendopeptidases
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Zmpste24 protein, mouse