Ndy1/KDM2B immortalizes mouse embryonic fibroblasts by repressing the Ink4a/Arf locus

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 8; pp. 2641 - 2646
• Main Authors: Tzatsos, Alexandros, Pfau, Raymond, Kampranis, Sotirios C, Tsichlis, Philip N
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 24.02.2009; National Acad Sciences
• Subjects: Animals; Biological Sciences; Cell Line, Transformed; Cellular Senescence; Cyclin-Dependent Kinase Inhibitor p16 - genetics; cyclin-dependent kinase inhibitors; DNA-directed RNA polymerase; Down regulation; Embryo fibroblasts; Enhancer of Zeste Homolog 2 Protein; Fibroblasts - cytology; Gene expression regulation; Gene Expression Regulation, Developmental - physiology; Gene silencing; Genetic loci; Histone H3; Histone-Lysine N-Methyltransferase - physiology; Histones; Histones - metabolism; Immortalization; INK4 protein; Messenger RNA; Methylation; Mice; Molecular modelling; Nuclear Proteins - physiology; Oxidoreductases, N-Demethylating - physiology; Polycomb Repressive Complex 1; Polycomb Repressive Complex 2; Proto-Oncogene Proteins - physiology; Ras protein; Repressor Proteins - physiology; RNA; Senescence; Stem cells; Up regulation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0813139106

The histone H3 demethylase Not dead yet-1 (Ndy1/KDM2B) is a physiological inhibitor of senescence. Here, we show that Ndy1 is down-regulated during senescence in mouse embryonic fibroblasts (MEFs) and that it represses the Ink4a/Arf locus. Ndy1 counteracts the senescence-associated down-regulation of Ezh2, a component of polycomb-repressive complex (PRC) 2, via a JmjC domain-dependent process leading to the global and Ink4a/Arf locus-specific up-regulation of histone H3K27 trimethylation. The latter promotes the Ink4a/Arf locus-specific binding of Bmi1, a component of PRC1. Ndy1, which interacts with Ezh2, also binds the Ink4a/Arf locus and demethylates the locus-associated histone H3K36me2 and histone H3K4me3. The combination of histone modifications driven by Ndy1 interferes with the binding of RNA Polymerase II, resulting in the transcriptional silencing of the Ink4a/Arf locus and contributing to the Ndy1 immortalization phenotype. Other studies show that, in addition to inhibiting replicative senescence, Ndy1 inhibits Ras oncogene-induced senescence via a similar molecular mechanism.