Epigenetic regulation of p16Ink4a and Arf by JDP2 in cellular senescence.

In response to accumulating cellular stress, cells protect themselves from abnormal growth by entering the senescent stage. Senescence is controlled mainly by gene products from the p16Ink4a/Arf locus. In mouse cells, the expression of p16Ink4a and Arf increases continuously during proliferation in cell culture. Transcription from the locus is under complex control. p16Ink4a and Arf respond independently to positive and negative signals, and the entire locus is epigenetically suppressed by histone methylation that depends on the Polycomb repressive complex-1 and -2 (PRC1 and PRC2). In fact, the PRCs associate with the p16Ink4a/Arf locus in young proliferating cells and dissociate in aged senescent cells. Thus, it seems that chromatin-remodeling factors that regulate association and dissociation of PRCs might be important players in the senescence program. Here, we summarize the molecular mechanisms that mediate cellular aging and introduce the Jun dimerization protein 2 (JDP2) as a factor that regulates replicative senescence by mediating dissociation of PRCs from the p16Ink4a/Arf locus.