301. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence.
- Author
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Narita M, Nũnez S, Heard E, Narita M, Lin AW, Hearn SA, Spector DL, Hannon GJ, and Lowe SW
- Subjects
- Binding Sites genetics, Cell Line, Cell Size genetics, DNA genetics, DNA metabolism, E2F Transcription Factors, Eukaryotic Cells ultrastructure, Fibroblasts metabolism, Fibroblasts ultrastructure, Gene Targeting, Genes, p16 physiology, Heterochromatin metabolism, Heterochromatin ultrastructure, Humans, Promoter Regions, Genetic genetics, Repressor Proteins genetics, Retinoblastoma Protein metabolism, Transcription Factors metabolism, Tumor Suppressor Proteins metabolism, Cell Cycle Proteins, Cellular Senescence genetics, DNA-Binding Proteins, Eukaryotic Cells metabolism, Gene Silencing physiology, Heterochromatin genetics, Retinoblastoma Protein genetics, Transcription Factors genetics, Tumor Suppressor Proteins genetics
- 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.
- Published
- 2003
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