Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence.

By Masashi Narita, S. Nũnez, Edith Heard, M. Narita, Athena W. Lin, Stephen A Hearn, David L. Spector, Gregory J. Hannon, Scott W. Lowe. Cell, 2003

2,280 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Oncology, Physiology

View Paper: https://www.semanticscholar.org/paper/a1b5c30ec33ee7f5802ec3ad499accf8521f36d6

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Citations in the corpus

Aging, Cellular Senescence, and Cancer (2012, background): “Some senescent cells contain senescence-associated heterochromatin foci (SAHF): cytologically detectable heterochromatin domains that also contain (and presumably silence) certain proproliferative genes (60).”
Living on a break: cellular senescence as a DNA-damage response (2008, background): “This mechanism has been proposed to be exploited by the cell to prevent transcription of E2F target genes, which are associated with cell-cycle entry and proliferatio”
Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. (2005, background): “Replicatively senescent cells develop dense foci of heterochromatin (Narita et al., 2003; Zhang et al., 2005) which coincide with pRBdependent heterochromatic repression of genes encoding cyclins and other positive cell cycle regulators (Bandyopadhyay et al., 2002; Narita et al., 2003).”
Senescence in tumours: evidence from mice and humans (2010, background): “This histone methyltransferase is involved in the formation of heterochromatin and could be relevant for the formation of senescence-associated heterochromatin foci (SAHF), which are domains of silenced chromatin considered important for the senescent phenotyp”
Senescence impairs successful reprogramming to pluripotent stem cells. (2009, background): “The reorganization of heterochromatin that gives rise to these foci results in a stable transcriptional repression of E2F target genes (Narita et al., 2003).”
Senescence-messaging secretome: SMS-ing cellular stress (2009, background): “OIS and replicative senescence share a number of characteristics, including an increase in senescence-associated β-galactosidase (SA-β-GAL) activity and the condensation of individual chromosomes into distinct heterochromatic bodies, called senescence-associated heterochromatic foci (SAHF”
Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. (2006, methodology): “…and Cell Death ELISA Cells plated on gelatin-coated coverslips were incubated with 5- bromo-20-deoxyuridine (BrdU; 100 mg/ml; Sigma) for 1 hr. Nuclei incorporating BrdU were visualized by immunolabeling using anti-BrdU antibody (Pharmingen; 1:400) as previously described (Narita et al., 2003).”
The profile of repeat‐associated histone lysine methylation states in the mouse epigenome (2005, background): “This epigenetic plasticity may be particularly important for modulating the differentiation potential of cloned embryos (Santos et al, 2003) and progenitor or stem cells (Baxter et al, 2004), or for protecting a normal cell from conversion to a neoplastic or senescent cell (Narita et al, 2003).”
Four faces of cellular senescence (2011, positive): “For example, senescent keratinocytes secrete the anti-angiogenic factor maspin (Nickoloff et al., 2004).”
Intrinsic tumour suppression (2004, background): “p53 and Rb then promote senescence by controlling a number of effectors, including p21CIP1/WAF1, PML, and various chromatin-modifying factors that produce a repressive state that buffers proliferative genes from mitogenic signallin”
Lamin B1 loss is a senescence-associated biomarker (2012, methodology): “Mice were treated and mRNA was collected and analyzed as described in Figure 4F.”
The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. (2007, methodology): “SA- -gal assays were performed as previously described (Narita et al. 2003).”
Accumulation of senescent cells in mitotic tissue of aging primates. (2007, background): “…senescence of cultured cells has been correlated to increased levels and aggregation of heterochromatin proteins HP1β, Me2-K9-H3, and Me3-K9-H3 (Narita et al., 2003; Zhang et al., 2005) we could not detect either specific staining or a statistically significant and age dependent increase of…”