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Histone H4 lysine 16 hypoacetylation is associated with defective DNA repair and premature senescence in Zmpste24-deficient mice
Open accessAbstract
Specific point mutations in lamin A gene have been shown to accelerate aging in humans and mice. Particularly, a de novo mutation at G608G position impairs lamin A processing to produce the mutant protein progerin, which causes the Hutchinson Gilford progeria syndrome. The premature aging phenotype of Hutchinson Gilford progeria syndrome is largely recapitulated in mice deficient for the lamin A-processing enzyme, Zmpste24. We have previously reported that Zmpste24 deficiency results in genomic instability and early cellular senescence due to the delayed recruitment of repair proteins to sites of DNA damage. Here, we further investigate the molecular mechanism underlying delayed DNA damage response and identify a histone acetylation defect in Zmpste24 −/− mice. Specifically, histone H4 was hypoacetylated at a lysine 16 residue (H4K16), and this defect was attributed to the reduced association of a histone acetyltransferase, Mof, to the nuclear matrix. Given the reversible nature of epigenetic changes, rescue experiments performed either by Mof overexpression or by histone deacetylase inhibition promoted repair protein recruitment to DNA damage sites and substantially ameliorated aging-associated phenotypes, both in vitro and in vivo. The life span of Zmpste24 −/− mice was also extended with the supplementation of a histone deacetylase inhibitor, sodium butyrate, to drinking water. Consistent with recent data showing age-dependent buildup of unprocessable lamin A in physiological aging, aged wild-type mice also showed hypoacetylation of H4K16. The above results shed light on how chromatin modifications regulate the DNA damage response and suggest that the reversal of epigenetic marks could make an attractive therapeutic target against laminopathy-based progeroid pathologies.
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“Inhibitors of histone acetyltransferases also ameliorate the premature aging phenotype and extend longevity of progeroid mice (Krishnan et al., 2011).”
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“Pharmacologic treatment that alters histone modification such as acetylation status also shows an effect on longevity in aging and progeroid mouse models, suggesting that potential future therapeutic interventions targeting epigenetic regulators may be feasible175,176.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [176]
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Metadata
- Authors
- Krishnan, V., Chow, M. Z. Y., Wang, Z., Zhang, L., Liu, B., Liu, X., & Zhou, Z.
- Affiliations
- National University of Singapore (SG)
- University of Hong Kong (HK)
- Shenzhen University (CN)
- Guangdong Medical College (CN)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-07-11
- Volume
- 108
- Issue
- 30
- Pages
- 12325-12330
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3145730
- OpenAlex
- W2162996266
- Cited by
- 236
- References
- 56
- Citations by year
- 2026: 13 · 2025: 8 · 2024: 12 · 2023: 8 · 2022: 11 · 2021: 15 · 2020: 19 · 2019: 15 · 2018: 21 · 2017: 11 · 2016: 20 · 2015: 21 · 2014: 18 · 2013: 19 · 2012: 22
- FWCI
- 8.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Funders
- National Natural Science Foundation of China (30871440, 30672205, 9252402301000002)
- Natural Science Foundation of Guangdong Province (9252402301000002)
- Innovation and Technology Fund
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- ZMPSTE24, Hutchinson-Gilford progeria syndrome, premature senescence, DNA repair, DNA damage response, histone deacetylase inhibition, sodium butyrate, laminopathies, premature aging, chromatin modification, nuclear matrix, genomic instability
- MeSH terms
- Tumor Suppressor p53-Binding Protein 1, Acetylation, Aging, Animals, Cells, Cultured, Chromosomal Proteins, Non-Histone, Disease Models, Animal, DNA Repair, DNA-Binding Proteins, Histones, Humans, Lysine, Membrane Proteins, Metalloendopeptidases, Nuclear Proteins, Protein Precursors, Nuclear Matrix, Cellular Senescence, Mice, Knockout, Aging, Premature, RNA, Small Interfering, Lamin Type A, Mice, Histone Acetyltransferases, Histone Deacetylase Inhibitors
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