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Nucleic Acids Research Advance Access published online on June 26, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp533
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© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gene Regulation, Chromatin and Epigenetics

Senescence delay and repression of p16INK4a by Lsh via recruitment of histone deacetylases in human diploid fibroblasts

Rui Zhou, Limin Han, Guodong Li and Tanjun Tong*

Research Center on Aging, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, People's Republic of China

*To whom correspondence should be addressed. Tel: +86 10 82801454; Fax: +86 10 82802931; Email: ttj{at}bjmu.edu.cn

Received November 12, 2008. Revised May 30, 2009. Accepted June 8, 2009.

Lymphoid specific helicase (Lsh) belongs to the family of SNF2/helicases. Disruption of Lsh leads to developmental growth retardation and premature aging in mice. However, the specific effect of Lsh on human cellular senescence remains unknown. Herein, we report that Lsh overexpression delays cell senescence by silencing p16INK4a in human fibroblasts. The patterns of p16INK4a and Lsh expression during cell senescence present the inverse correlation. We also find that Lsh requires histone deacetylase (HDAC) activity to repress p16INK4a and treatment with trichostatin A (TSA) is sufficient to block the repressor effect of Lsh. Moreover, overexpression of Lsh is correlated with deacetylation of histone H3 at the p16 promoter, and TSA treatment in Lsh-expressing cells reverses the acetylation status of histones. Additionally, we demonstrate an interaction between Lsh, histone deacetylase 1 (HDAC1) and HDAC2 in vivo. Furthermore, we demonstrate that Lsh interacts in vivo with the p16 promoter and recruits HDAC1. Our data suggest that Lsh represses endogenous p16INK4a expression by recruiting HDAC to establish a repressive chromatin structure at the p16INK4a promoter, which in turn delays cell senescence.


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