Ndy1/KDM2B immortalizes mouse embryonic fibroblasts by repressing the Ink4a/Arf locus.
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.
Tzatsos
Alexandros
A
Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
Pfau
Raymond
R
Kampranis
Sotirios C
SC
Tsichlis
Philip N
PN
D000818:Animals; D002461:Cell Line, Transformed; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D000071221:Enhancer of Zeste Homolog 2 Protein; D005347:Fibroblasts / Q000166:cytology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D011495:Histone-Lysine N-Methyltransferase / Q000502:physiology; D006657:Histones / Q000378:metabolism; D008745:Methylation; D051379:Mice; D009687:Nuclear Proteins / Q000502:physiology; D010089:Oxidoreductases, N-Demethylating / Q000502:physiology*; D063150:Polycomb Repressive Complex 1; D063151:Polycomb Repressive Complex 2; D011518:Proto-Oncogene Proteins / Q000502:physiology; D012097:Repressor Proteins / Q000502:physiology; D015854:Up-Regulation
C489421:Bmi1 protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D006657:Histones; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C534140:Ndy1 protein, mouse; D010089:Oxidoreductases, N-Demethylating; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; D063150:Polycomb Repressive Complex 1