title: Histone H4 lysine 16 hypoacetylation is associated with defective DNA repair and premature senescence in Zmpste24-deficient mice.
abstract: 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.
authors: Department of Biochemistry, University of Hong Kong, Hong Kong.
authors: Vaidehi
authors: V
authors: Krishnan
authors: Maggie Zi Ying
authors: MZ
authors: Chow
authors: Zimei
authors: Z
authors: Wang
authors: Le
authors: L
authors: Zhang
authors: Baohua
authors: B
authors: Liu
authors: Xinguang
authors: X
authors: Liu
authors: Zhongjun
authors: Z
authors: Zhou
mesh_terms: D000107:Acetylation; D000375:Aging / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D019588:Aging, Premature / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D051548:Histone Acetyltransferases / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D034904:Lamin Type A; D008239:Lysine / Q000737:chemistry; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D008666:Metalloendopeptidases / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D015530:Nuclear Matrix / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D034904:Lamin Type A; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011498:Protein Precursors; D034741:RNA, Small Interfering; C498302:Trp53bp1 protein, mouse; D000071857:Tumor Suppressor p53-Binding Protein 1; C090764:prelamin A; D051548:Histone Acetyltransferases; C000622683:Kat8 protein, mouse; D008666:Metalloendopeptidases; C491250:Zmpste24 protein, mouse; D008239:Lysine