Please use this identifier to cite or link to this item: https://doi.org/10.1073/pnas.1102789108
Title: Histone H4 lysine 16 hypoacetylation is associated with defective DNA repair and premature senescence in Zmpste24-deficient mice
Authors: Krishnan, V. 
Chow, M.Z.Y.
Wang, Z.
Zhang, L.
Liu, B.
Liu, X.
Zhou, Z.
Issue Date: 26-Jul-2011
Citation: Krishnan, V., Chow, M.Z.Y., Wang, Z., Zhang, L., Liu, B., Liu, X., Zhou, Z. (2011-07-26). Histone H4 lysine 16 hypoacetylation is associated with defective DNA repair and premature senescence in Zmpste24-deficient mice. Proceedings of the National Academy of Sciences of the United States of America 108 (30) : 12325-12330. ScholarBank@NUS Repository. https://doi.org/10.1073/pnas.1102789108
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.
Source Title: Proceedings of the National Academy of Sciences of the United States of America
URI: http://scholarbank.nus.edu.sg/handle/10635/115135
ISSN: 00278424
DOI: 10.1073/pnas.1102789108
Appears in Collections:Staff Publications

Show full item record
Files in This Item:
There are no files associated with this item.

SCOPUSTM   
Citations

108
checked on Jun 16, 2018

WEB OF SCIENCETM
Citations

105
checked on May 30, 2018

Page view(s)

31
checked on Apr 20, 2018

Google ScholarTM

Check

Altmetric


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.