Tzatsos Alexandros, Pfau Raymond, Kampranis Sotirios C, Tsichlis Philip N
Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2641-6. doi: 10.1073/pnas.0813139106. Epub 2009 Feb 6.
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.
组蛋白H3去甲基化酶“尚未死亡”1（Ndy1/KDM2B）是衰老的生理抑制剂。在此，我们表明Ndy1在小鼠胚胎成纤维细胞（MEF）衰老过程中表达下调，并且它抑制Ink4a/Arf基因座。Ndy1通过一个依赖JmjC结构域的过程抵消衰老相关的Ezh2下调，Ezh2是多梳抑制复合物（PRC）2的一个组分，该过程导致组蛋白H3K27三甲基化在整体水平和Ink4a/Arf基因座特异性上调。后者促进PRC1组分Bmi1在Ink4a/Arf基因座的特异性结合。与Ezh2相互作用的Ndy1也结合Ink4a/Arf基因座，并使与该基因座相关的组蛋白H3K36me2和组蛋白H3K4me3去甲基化。由Ndy1驱动的组蛋白修饰组合干扰RNA聚合酶II的结合，导致Ink4a/Arf基因座的转录沉默，并促成Ndy1永生化表型。其他研究表明，除了抑制复制性衰老外，Ndy1还通过类似的分子机制抑制Ras癌基因诱导的衰老。
