MeCP2: structure and functionThis paper is one of a selection of papers published in a Special Issue entitled 31st Annual International Asilomar Chromatin and Chromosomes Conference, and has undergone the Journal’s usual peer review process.

Adkins, Nicholas L.; Georgel, Philippe

doi:10.1139/o10-112

Cited by 84 publications

(39 citation statements)

References 89 publications

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“…2, see MECP2 – HDAC complex). The complex acts by removing certain acetyl groups from histone proteins leading to chromatin condensation around methylated DNA [58, 59]. Cell culture experiments with an inhibitor of HDAC resulted in the same phenotype as MECP2-KO cells [60].…”

Section: Mecp2 As Epigenetic Regulatormentioning

confidence: 99%

Rett syndrome – biological pathways leading from MECP2 to disorder phenotypes

Ehrhart

Coort

Cirillo

et al. 2016

Orphanet J Rare Dis

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Rett syndrome (RTT) is a rare disease but still one of the most abundant causes for intellectual disability in females. Typical symptoms are onset at month 6–18 after normal pre- and postnatal development, loss of acquired skills and severe intellectual disability. The type and severity of symptoms are individually highly different. A single mutation in one gene, coding for methyl-CpG-binding protein 2 (MECP2), is responsible for the disease. The most important action of MECP2 is regulating epigenetic imprinting and chromatin condensation, but MECP2 influences many different biological pathways on multiple levels although the molecular pathways from gene to phenotype are currently not fully understood. In this review the known changes in metabolite levels, gene expression and biological pathways in RTT are summarized, discussed how they are leading to some characteristic RTT phenotypes and therefore the gaps of knowledge are identified. Namely, which phenotypes have currently no mechanistic explanation leading back to MECP2 related pathways? As a result of this review the visualization of the biologic pathways showing MECP2 up- and downstream regulation was developed and published on WikiPathways which will serve as template for future omics data driven research. This pathway driven approach may serve as a use case for other rare diseases, too.

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Section: Mecp2 As Epigenetic Regulatormentioning

confidence: 99%

Rett syndrome – biological pathways leading from MECP2 to disorder phenotypes

Ehrhart

Coort

Cirillo

et al. 2016

Orphanet J Rare Dis

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“…23 Explanations for the effect of the naturally occurring mutations responsible for Rett syndrome and other neurological disorders have been based upon binding studies conducted under a variety of solution conditions. 5,6,11,19,24 In addition, MeCP2 domains C-terminal to the MBD are extensively disordered 25,26 and restructure upon the protein binding mCpG sites. 9,22,26 These conformational changes are postulated to allosterically influence interaction of MeCP2 with other regulatory proteins.…”

mentioning

confidence: 99%

“…9,22,26 These conformational changes are postulated to allosterically influence interaction of MeCP2 with other regulatory proteins. 25,26 Delineation of mCpG binding specificity will allow further insight into the molecular dysfunction caused by disease mutations and whether allosteric transitions are linked to the precise nature of the bound DNA.…”

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confidence: 99%

Unusual Characteristics of the DNA Binding Domain of Epigenetic Regulatory Protein MeCP2 Determine Its Binding Specificity

et al. 2014

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The protein MeCP2 mediates epigenetic regulation by binding methyl-CpG (mCpG) sites on chromatin. MeCP2 consists of six domains of which one, the methyl binding domain (MBD), binds mCpG sites in duplex DNA. We show that solution conditions with physiological or greater salt concentrations or the presence of nonspecific competitor DNA is necessary for the MBD to discriminate mCpG from CpG with high specificity. The specificity for mCpG over CpG is >100-fold under these solution conditions. In contrast, the MBD does not discriminate hydroxymethyl-CpG from CpG. The MBD is unusual among site-specific DNA binding proteins in that (i) specificity is not conferred by the enhanced affinity for the specific site but rather by suppression of its affinity for generic DNA, (ii) its specific binding to mCpG is highly electrostatic, and (iii) it takes up as well as displaces monovalent cations upon DNA binding. The MBD displays an unusually high affinity for single-stranded DNA independent of modification or sequence. In addition, the MBD forms a discrete dimer on DNA via a noncooperative binding pathway. Because the affinity of the second monomer is 1 order of magnitude greater than that of nonspecific binding, the MBD dimer is a unique molecular complex. The significance of these results in the context of neuronal function and development and MeCP2-related developmental disorders such as Rett syndrome is discussed.

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“…Although CDC20B has not been widely investigated, both MECP2 and CDC20B are considered to be crucial in tumor progression 18–20. MECP2 was the first identified member of the methylated DNA binding proteins and is an important regulatory factor in gene expression, and has been classically described as a global transcription repressor 21. As a transcriptional repressor, MECP2 contains two functional domains, ie, a methylated DNA binding domain and a transcriptional repression domain, both of which are involved in the regulation of transcription activity, especially for tumor suppressor genes, thus plays an important role in the development of cancer 19,21.…”

Section: Discussionmentioning

confidence: 99%

Antitumor activity of SA12, a novel peptide, on SKBr-3 breast cancer cells via the mitochondrial apoptosis pathway

Yang

Cui

Shen

et al. 2015

DDDT

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Breast cancer is considered to be the most common malignancy in women. Treatment of breast cancer has been focused on molecular targeted therapy, and anticancer peptides are considered to be some of the most promising candidate drugs. In the current study, we used mRNA-peptide display technology to screen antibreast cancer peptides and identified a novel peptide, SA12, which showed significant activity in the inhibition of proliferation and induction of apoptosis in SKBr-3 breast cancer cells. The mechanism by which SA12 peptide triggers apoptosis was further investigated using a pull-down assay, reverse transcription-polymerase chain reaction, and Western blotting analysis. The results demonstrated that this peptide could interact with tumor-associated proteins MECP2 and CDC20B, which further induced apoptosis of tumor cells via the mitochondrial pathway involving the Bcl-2 family and related caspases. We propose that the novel SA12 peptide has the potential to provide a new strategy for the development of targeted therapy in breast cancer.

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MeCP2: structure and functionThis paper is one of a selection of papers published in a Special Issue entitled 31st Annual International Asilomar Chromatin and Chromosomes Conference, and has undergone the Journal’s usual peer review process.

Cited by 84 publications

References 89 publications

Rett syndrome – biological pathways leading from MECP2 to disorder phenotypes

Rett syndrome – biological pathways leading from MECP2 to disorder phenotypes

Unusual Characteristics of the DNA Binding Domain of Epigenetic Regulatory Protein MeCP2 Determine Its Binding Specificity

Antitumor activity of SA12, a novel peptide, on SKBr-3 breast cancer cells via the mitochondrial apoptosis pathway

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