DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters

  title={DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters},
  author={Keith D. Robertson and Slimane Ait-Si-Ali and Tomoki Yokochi and Paul A. Wade and Peter L Jones and Alan P. Wolffe},
  journal={Nature Genetics},
Methylation of CpG islands is associated with transcriptional silencing and the formation of nuclease-resistant chromatin structures enriched in hypoacetylated histones. Methyl-CpG-binding proteins, such as MeCP2, provide a link between methylated DNA and hypoacetylated histones by recruiting histone deacetylase, but the mechanisms establishing the methylation patterns themselves are unknown. Whether DNA methylation is always causal for the assembly of repressive chromatin or whether features… 

Altered chromatin structure associated with methylation-induced gene silencing in cancer cells: correlation of accessibility, methylation, MeCP2 binding and acetylation.

An altered chromatin structure associated with the silencing of tumor-suppressor genes in human cancer cell lines is demonstrated and it is demonstrated that CpG islands located in promoters versus exons display marked differences in the levels of acetylation of associated histone H3, suggesting that chromatin remodeling can be achieved by methylation-independent processes.

Methyl-CpG-binding Protein, MeCP2, Is a Target Molecule for Maintenance DNA Methyltransferase, Dnmt1*

The results suggest that Dnmt1 associates with MeCP2 in order to perform maintenance methylation in vivo, and propose that genome-wide and/or -specific local DNA methylation may be maintained by the DnMT1-MeCP2 complexes, bound to hemimethylated DNA.

Methylation-mediated Silencing of TMS1/ASC Is Accompanied by Histone Hypoacetylation and CpG Island-localized Changes in Chromatin Architecture*

The data indicate that there are sites of protein binding and/or structural transitions that define the boundaries of the unmethylated CpG island in normal cells and that aberrant methylation overcomes these boundaries to direct a local change in chromatin structure, resulting in gene silencing.

Histone H3-lysine 9 methylation is associated with aberrant gene silencing in cancer cells and is rapidly reversed by 5-aza-2'-deoxycytidine.

Using the chromatin immunoprecipitation (ChIP) assay, it is demonstrated that aberrantly silenced genes in cancer cells exhibit a heterochromatic structure that is characterized by histone H3 lysine 9 (H3-K9) hypermethylation and histone Lysine 4 (H 3-K4) hypomethylation, which may play a role in the silencing of tumor-suppressor genes incancer.

Dnmt3a binds deacetylases and is recruited by a sequence‐specific repressor to silence transcription

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Chromatin Inactivation Precedes De Novo DNA Methylation during the Progressive Epigenetic Silencing of the RASSF1A Promoter

The data suggest that in epithelial cells, histone inactivation may trigger de novo DNA methylation of the RASSF1A promoter and this system may serve as a model for CpG island inactivation of tumor suppressor genes.

The retinoblastoma gene product interacts with maintenance human DNA (cytosine‐5) methyltransferase and modulates its activity

Overexpression of Rb leads to hypomethylation of the cellular DNA, suggesting that Rb may modulate Dnmt1 activity during DNA replication in the cell cycle.

DNA methylation, chromatin inheritance, and cancer

Understanding the molecular determinants of both normal and abnormal patterns of chromatin formation and DNA methylation holds great promise for the understanding of cancer and for means to better diagnose, prevent, and treat this disease.

DNMT1 Stability Is Regulated by Proteins Coordinating Deubiquitination and Acetylation-Driven Ubiquitination

A previously unknown mode of regulation ofDNMT1 protein stability through the coordinated action of an array of DNMT1-associated proteins is described, providing a mechanism-based rationale for the development of HDAC and HAUSP inhibitors for combined use in cancer therapy.



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The data suggest that two global mechanisms of gene regulation, DNA methylation and histone deacetylation, can be linked by MeCP2, an abundant nuclear protein that is essential for mouse embryogenesis.

DNA methyltransferase Dnmt1 associates with histone deacetylase activity

A transcriptional repression domain in Dnmt1 is identified that functions, at least partly, by recruiting histone deacetylase activity and shows homology to the repressor domain of the trithorax-related protein HRX (also known as MLL and ALL-1).

Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription

The results establish a direct causal relationship between DNA methylation-dependent transcriptional silencing and the modification of chromatin.

Retinoblastoma protein represses transcription by recruiting a histone deacetylase

It is shown here that the histone deacetylase HDAC1 physically interacts and cooperates with Rb, and that the Rb/HDAC1 complex is a key element in the control of cell proliferation and differentiation and that it is a likely target for transforming viruses.

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Investigation of the expression of human DNMT1, 3a and 3b found widespread, coordinate expression of all three transcripts in most normal tissues, and several novel alternatively spliced forms of DNMT3b, which may have altered enzymatic activity, were found to be expressed in a tissue-specific manner.

The Human ARF Cell Cycle Regulatory Gene Promoter Is a CpG Island Which Can Be Silenced by DNA Methylation and Down-Regulated by Wild-Type p53

The clone and characterize the promoter of the human ARF gene and show that it is a CpG island characteristic of a housekeeping gene which contains numerous Sp1 sites, which points to the existence of an autoregulatory feedback loop between p53, MDM2, and ARF, aimed at keeping p53 levels in check.

The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome.

The first example of naturally occurring mutations in a mammalian DNA methyltransferase gene is described, occurring in patients with a rare autosomal recessive disorder, termed the ICF syndrome, for immunodeficiency, centromeric instability, and facial anomalies.

Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1.

DNA-(cytosine-5) methyltransferase (MCMT) methylates newly replicated mammalian DNA, but the factors regulating this activity are unknown. Here, MCMT is shown to bind proliferating cell nuclear