Rb-mediated Heterochromatin Formation and Silencing of E2F Target Genes During Cellular Senescence

Cell. 2003 Jun 13;113(6):703-16. doi: 10.1016/s0092-8674(03)00401-x.

Abstract

Cellular senescence is an extremely stable form of cell cycle arrest that limits the proliferation of damaged cells and may act as a natural barrier to cancer progression. In this study, we describe a distinct heterochromatic structure that accumulates in senescent human fibroblasts, which we designated senescence-associated heterochromatic foci (SAHF). SAHF formation coincides with the recruitment of heterochromatin proteins and the retinoblastoma (Rb) tumor suppressor to E2F-responsive promoters and is associated with the stable repression of E2F target genes. Notably, both SAHF formation and the silencing of E2F target genes depend on the integrity of the Rb pathway and do not occur in reversibly arrested cells. These results provide a molecular explanation for the stability of the senescent state, as well as new insights into the action of Rb as a tumor suppressor.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Binding Sites / genetics
  • Cell Cycle Proteins*
  • Cell Line
  • Cell Size / genetics
  • Cellular Senescence / genetics*
  • DNA / genetics
  • DNA / metabolism
  • DNA-Binding Proteins*
  • E2F Transcription Factors
  • Eukaryotic Cells / metabolism*
  • Eukaryotic Cells / ultrastructure
  • Fibroblasts / metabolism
  • Fibroblasts / ultrastructure
  • Gene Silencing / physiology*
  • Gene Targeting
  • Genes, p16 / physiology
  • Heterochromatin / genetics*
  • Heterochromatin / metabolism
  • Heterochromatin / ultrastructure
  • Humans
  • Promoter Regions, Genetic / genetics
  • Repressor Proteins / genetics
  • Retinoblastoma Protein / genetics*
  • Retinoblastoma Protein / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • E2F Transcription Factors
  • Heterochromatin
  • Repressor Proteins
  • Retinoblastoma Protein
  • Transcription Factors
  • Tumor Suppressor Proteins
  • DNA