Cyclin-dependent kinases regulate epigenetic gene silencing through phosphorylation of EZH2

Chen, Shuai; Bohrer, Laura R.; Aswathy, N.; Pan, Yunqian; Gan, Lu; Zhou, Xianzheng; Bagchi, Anindya; Simon, John; Huang, Haojie

doi:10.1038/ncb2116

Cited by 225 publications

(243 citation statements)

References 38 publications

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“…This is consistent with a model whereby PRC2 is recruited to specific genes to initiate repression as a function of its Ezh2 component being phosphorylated at T345, after which other PRC2 complexes then spread the repressing signature (H3K27me2/3) (see below). Of note, a recent study has also documented that human Ezh2 is phosphorylated at Thr 350 (murine T345) by CDK1, and, in agreement with our findings, the report shows that this modification is ineffectual with respect to the integrity of the PRC2 complex and PRC2-mediated HKMT activity (Chen et al 2010). Instead, this study shows that mutant Ezh2 that is not subject to T350 phosphorylation results in down-regulated PRC2 recruitment, such that appropriate gene repression is thwarted.…”

Section: Discussionsupporting

confidence: 77%

Phosphorylation of the PRC2 component Ezh2 is cell cycle-regulated and up-regulates its binding to ncRNA

Kaneko¹,

Li²,

Son³

et al. 2010

Genes Dev.

333

370

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Ezh2 functions as a histone H3 Lys 27 (H3K27) methyltransferase when comprising the Polycomb-Repressive Complex 2 (PRC2). Trimethylation of H3K27 (H3K27me3) correlates with transcriptionally repressed chromatin. The means by which PRC2 targets specific chromatin regions is currently unclear, but noncoding RNAs (ncRNAs) have been shown to interact with PRC2 and may facilitate its recruitment to some target genes. Here we show that Ezh2 interacts with HOTAIR and Xist. Ezh2 is phosphorylated by cyclin-dependent kinase 1 (CDK1) at threonine residues 345 and 487 in a cell cycle-dependent manner. A phospho-mimic at residue 345 increased HOTAIR ncRNA binding to Ezh2, while the phospho-mimic at residue 487 was ineffectual. An Ezh2 domain comprising T345 was found to be important for binding to HOTAIR and the 5′ end of Xist.

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Section: Discussionsupporting

confidence: 77%

Phosphorylation of the PRC2 component Ezh2 is cell cycle-regulated and up-regulates its binding to ncRNA

Kaneko¹,

Li²,

Son³

et al. 2010

Genes Dev.

333

370

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show abstract

“…So, it is possible that a dysfunctional Pol d may disturb the entire replication machinery, which would interfere with the recruitment of LHP1 or PcG proteins to PcG targets. In mammalian cells, PcG proteins can be phosphorylated by cyclin-dependent kinases in a cell cycle-dependent manner (Chen et al, 2010). Because pold2-1 exhibits an abnormal cell cycle (Fig.…”

Section: Discussionmentioning

confidence: 99%

The second subunit of DNA-polymerase delta is required for genomic stability and epigenetic regulation

et al. 2016

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ORCID IDs: 0000-0002-1641-8650 (J.Z.); 0000-0002-6719-9814 (S.X.); 0000-0001-5134-731X (J.-K.Z.).DNA polymerase d plays crucial roles in DNA repair and replication as well as maintaining genomic stability. However, the function of POLD2, the second small subunit of DNA polymerase d, has not been characterized yet in Arabidopsis (Arabidopsis thaliana). During a genetic screen for release of transcriptional gene silencing, we identified a mutation in POLD2. Whole-genome bisulfite sequencing indicated that POLD2 is not involved in the regulation of DNA methylation. POLD2 genetically interacts with Ataxia Telangiectasia-mutated and Rad3-related and DNA polymerase a. The pold2-1 mutant exhibits genomic instability with a high frequency of homologous recombination. It also exhibits hypersensitivity to DNA-damaging reagents and short telomere length. Whole-genome chromatin immunoprecipitation sequencing and RNA sequencing analyses suggest that pold2-1 changes H3K27me3 and H3K4me3 modifications, and these changes are correlated with the gene expression levels. Our study suggests that POLD2 is required for maintaining genome integrity and properly establishing the epigenetic markers during DNA replication to modulate gene expression.

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“…Certainly, marking chromatin epigenetically is known to be accomplished by targets of CDK regulation. For example, mammalian CDK1 and CDK2 phosphorylate a Polycomb group protein, enhancer of zeste homolog 2, which has an essential role in promoting histone H3 Lys-27 trimethylation and thereby in the silencing of developmental regulators (Chen et al, 2010). In bryophytes, reprogramming of wounded gametophore cells is physiologically relevant.…”

Section: Acquisition Of Chloronema-specific Characteristics At S-phasementioning

confidence: 99%

PhyscomitrellaCyclin-Dependent Kinase A Links Cell Cycle Reactivation to Other Cellular Changes during Reprogramming of Leaf Cells

et al. 2011

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During regeneration, differentiated plant cells can be reprogrammed to produce stem cells, a process that requires coordination of cell cycle reactivation with acquisition of other cellular characteristics. However, the factors that coordinate the two functions during reprogramming have not been determined. Here, we report a link between cell cycle reactivation and the acquisition of new cell-type characteristics through the activity of cyclin-dependent kinase A (CDKA) during reprogramming in the moss Physcomitrella patens. Excised gametophore leaf cells of P. patens are readily reprogrammed, initiate tip growth, and form chloronema apical cells with stem cell characteristics at their first cell division. We found that leaf cells facing the cut undergo CDK activation along with induction of a D-type cyclin, tip growth, and transcriptional activation of protonema-specific genes. A DNA synthesis inhibitor, aphidicolin, inhibited cell cycle progression but prevented neither tip growth nor protonemal gene expression, indicating that cell cycle progression is not required for acquisition of protonema cell-type characteristics. By contrast, treatment with a CDK inhibitor or induction of dominant-negative CDKA;1 protein inhibited not only cell cycle progression but also tip growth and protonemal gene expression. These findings indicate that cell cycle progression is coordinated with other cellular changes by the concomitant regulation through CDKA;1.

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Cyclin-dependent kinases regulate epigenetic gene silencing through phosphorylation of EZH2

Cited by 225 publications

References 38 publications

Phosphorylation of the PRC2 component Ezh2 is cell cycle-regulated and up-regulates its binding to ncRNA

Phosphorylation of the PRC2 component Ezh2 is cell cycle-regulated and up-regulates its binding to ncRNA

The second subunit of DNA-polymerase delta is required for genomic stability and epigenetic regulation

PhyscomitrellaCyclin-Dependent Kinase A Links Cell Cycle Reactivation to Other Cellular Changes during Reprogramming of Leaf Cells

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