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

Nucleic Acids Res. 2009 Aug;37(15):5183-96. doi: 10.1093/nar/gkp533. Epub 2009 Jun 26.


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 p16(INK4a) in human fibroblasts. The patterns of p16(INK4a) and Lsh expression during cell senescence present the inverse correlation. We also find that Lsh requires histone deacetylase (HDAC) activity to repress p16(INK4a) 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 p16(INK4a) expression by recruiting HDAC to establish a repressive chromatin structure at the p16(INK4a) promoter, which in turn delays cell senescence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Cell Proliferation
  • Cellular Senescence / genetics*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Helicases / antagonists & inhibitors
  • DNA Helicases / genetics
  • DNA Helicases / metabolism*
  • Diploidy
  • Fibroblasts / cytology
  • Fibroblasts / enzymology
  • Fibroblasts / metabolism
  • G1 Phase
  • Gene Silencing*
  • Heterochromatin / chemistry
  • Histone Deacetylase 1
  • Histone Deacetylase 2
  • Histone Deacetylases / metabolism*
  • Humans
  • Promoter Regions, Genetic
  • Repressor Proteins / metabolism
  • beta-Galactosidase / metabolism


  • Cyclin-Dependent Kinase Inhibitor p16
  • Heterochromatin
  • Repressor Proteins
  • DNA (Cytosine-5-)-Methyltransferases
  • beta-Galactosidase
  • HDAC1 protein, human
  • Hdac2 protein, mouse
  • Histone Deacetylase 1
  • Histone Deacetylase 2
  • Histone Deacetylases
  • DNA Helicases
  • HELLS protein, human