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Article: Histone H4 lysine 16 hypoacetylation is associated with defective DNA repair and premature senescence in Zmpste24-deficient mice

TitleHistone H4 lysine 16 hypoacetylation is associated with defective DNA repair and premature senescence in Zmpste24-deficient mice
Authors
Issue Date2011
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
Citation
Proceedings Of The National Academy Of Sciences Of The United States Of America, 2011, v. 108 n. 30, p. 12325-12330 How to Cite?
AbstractSpecific 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.
Persistent Identifierhttp://hdl.handle.net/10722/138966
ISSN
2015 Impact Factor: 9.423
2015 SCImago Journal Rankings: 6.883
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Research Grant Council of Hong KongHKU7698/05M
HKU7655/06M
HKU 781707M
CRF HKU3/07C
Hong Kong Progeria Research FoundationITS/102/07
Natural Science Foundation of China30672205
30871440
30971620
Ministry of Science and Technology of China2007CB50740
2011CB964700
Natural Science Foundation of Guangdong Province8452402301001450
9252402301000002
Science and Technology Planning Project from Dongguan City2008108101045
Funding Information:

This work was supported by the Research Grant Council of Hong Kong (HKU7698/05M, HKU7655/06M, HKU 781707M, CRF HKU3/07C), the Innovation and Technology Fund of Hong Kong (ITS/102/07) Progeria Research Foundation, the Natural Science Foundation of China (30672205, 30871440, 30971620), and the Ministry of Science and Technology of China (973 Projects 2007CB50740, 2011CB964700). The authors acknowledge support from the Natural Science Foundation of Guangdong Province (8452402301001450, 9252402301000002) and the Science and Technology Planning Project (2008108101045) from Dongguan City.

References
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DC FieldValueLanguage
dc.contributor.authorKrishnan, Ven_HK
dc.contributor.authorChow, MZYen_HK
dc.contributor.authorWang, Zen_HK
dc.contributor.authorZhang, Len_HK
dc.contributor.authorLiu, Ben_HK
dc.contributor.authorLiu, Xen_HK
dc.contributor.authorZhou, Zen_HK
dc.date.accessioned2011-09-23T05:43:17Z-
dc.date.available2011-09-23T05:43:17Z-
dc.date.issued2011en_HK
dc.identifier.citationProceedings Of The National Academy Of Sciences Of The United States Of America, 2011, v. 108 n. 30, p. 12325-12330en_HK
dc.identifier.issn0027-8424en_HK
dc.identifier.urihttp://hdl.handle.net/10722/138966-
dc.description.abstractSpecific 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.en_HK
dc.languageengen_US
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.orgen_HK
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of Americaen_HK
dc.rightsNational Academy of Sciences. Proceedings. Copyright © National Academy of Sciences.-
dc.subject.meshAging, Premature - genetics - metabolism-
dc.subject.meshDNA Repair-
dc.subject.meshHistones - chemistry - metabolism-
dc.subject.meshMembrane Proteins - deficiency - genetics-
dc.subject.meshMetalloendopeptidases - deficiency - genetics-
dc.titleHistone H4 lysine 16 hypoacetylation is associated with defective DNA repair and premature senescence in Zmpste24-deficient miceen_HK
dc.typeArticleen_HK
dc.identifier.emailLiu, B:ppliew@hkusua.hku.hken_HK
dc.identifier.emailZhou, Z:zhongjun@hkucc.hku.hken_HK
dc.identifier.authorityLiu, B=rp01485en_HK
dc.identifier.authorityZhou, Z=rp00503en_HK
dc.identifier.doi10.1073/pnas.1102789108en_HK
dc.identifier.pmid21746928-
dc.identifier.pmcidPMC3145730-
dc.identifier.scopuseid_2-s2.0-79961083402en_HK
dc.identifier.hkuros194493en_US
dc.identifier.hkuros190281-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79961083402&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume108en_HK
dc.identifier.issue30en_HK
dc.identifier.spage12325en_HK
dc.identifier.epage12330en_HK
dc.identifier.eissn1091-6490-
dc.identifier.isiWOS:000293129900031-
dc.publisher.placeUnited Statesen_HK
dc.relation.projectLamin C in development and tumorigenesis-
dc.relation.projectScreening anti-ageing substances in small chemical library using premature ageing animals-
dc.identifier.scopusauthoridKrishnan, V=53363559000en_HK
dc.identifier.scopusauthoridChow, MZY=53363256600en_HK
dc.identifier.scopusauthoridWang, Z=53364870000en_HK
dc.identifier.scopusauthoridZhang, L=53364663200en_HK
dc.identifier.scopusauthoridLiu, B=7408693394en_HK
dc.identifier.scopusauthoridLiu, X=53364021400en_HK
dc.identifier.scopusauthoridZhou, Z=8631856300en_HK
dc.identifier.citeulike9941668-

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