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Nobuhiro Sasai Mitsuyoshi Nakao Pierre-Antoine Defossez 《Nucleic acids research》2010,38(15):5015-5022
DNA methylation is an essential epigenetic mark. Three classes of mammalian proteins recognize methylated DNA: MBD proteins, SRA proteins and the zinc-finger proteins Kaiso, ZBTB4 and ZBTB38. The last three proteins can bind either methylated DNA or unmethylated consensus sequences; how this is achieved is largely unclear. Here, we report that the human zinc-finger proteins Kaiso, ZBTB4 and ZBTB38 can bind methylated DNA in a sequence-specific manner, and that they may use a mode of binding common to other zinc-finger proteins. This suggests that many other sequence-specific methyl binding proteins may exist. 相似文献
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Caitlyn W. Barrett J. Joshua Smith Lauren C. Lu Nicholas Markham Kristy R. Stengel Sarah P. Short Baolin Zhang Aubrey A. Hunt Barbara M. Fingleton Robert H. Carnahan Michael E. Engel Xi Chen R. Daniel Beauchamp Keith T. Wilson Scott W. Hiebert Albert B. Reynolds Christopher S. Williams 《PloS one》2012,7(12)
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V. M. Pekhov A. M. Mazur E. B. Prokhorchuk 《Applied Biochemistry and Microbiology》2010,46(7):688-696
The methods for synthesis and application of resins based on the functional domains of Kaiso and CpG-binding protein (CGBP),
which can bind methylated and unmethylated CpG-dinucleotides, respectively, are shown. Kaiso resin was obtained by the affinity
interaction of glutathione-sepharose with a chimeric protein, which is expressed in Escherichia coli and contain glutathione S-transferase (GST) and zinc finger domain of methyl-DNA-binding Kaiso protein within the same translation
frame. Kaiso resin, like MBD-domain based resin, has an ability to bind methylated DNA. Experiments with the short DNA fragments
demonstrated that methylated DNA is eluted from the resin by 0.7 M KCl, whereas unmethylated DNA is washed out by 0.2–0.5
M KCl after binding. Quantitative PCR showed that the enrichment with methylated p16 promoter region and the absence of accumulation of γ-actin unmethylated promoter were observed due to the binding of genomic
DNA, isolated from the colo 320 cell line (human colorectal adenocarcinoma), with the Kaiso resin. The CGBP resin based on the CxxC domain of CGBP protein
binds to the sequences which contain unmethylated CpG-dinucleotides. Our experiments also showed no effect of MBD3L1 protein
on MBD2-resin capacity of binding with methylated DNA. The obtained resins can be applied to study methylation status of both
specific DNA sequences and the whole genome. 相似文献
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DNA methylation is an epigenetic mark that is essential for the development of mammals; it is frequently altered in diseases ranging from cancer to psychiatric disorders. The presence of DNA methylation attracts specialized methyl-DNA binding factors that can then recruit chromatin modifiers. These methyl-CpG binding proteins (MBPs) have key biological roles and can be classified into three structural families: methyl-CpG binding domain (MBD), zinc finger, and SET and RING finger-associated (SRA) domain. The structures of MBD and SRA proteins bound to methylated DNA have been previously determined and shown to exhibit two very different modes of methylated DNA recognition. The last piece of the puzzle has been recently revealed by the structural resolution of two different zinc finger proteins, Kaiso and ZFP57, in complex with methylated DNA. These structures show that the two methyl-CpG binding zinc finger proteins adopt differential methyl-CpG binding modes. Nonetheless, there are similarities with the MBD proteins suggesting some commonalities in methyl-CpG recognition across the various MBP domains. These fresh insights have consequences for the analysis of the many other zinc finger proteins present in the genome, and for the biology of methyl-CpG binding zinc finger proteins. 相似文献
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Methyl-CpG-binding proteins. Targeting specific gene repression. 总被引:25,自引:0,他引:25
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Jason M. Cramer J. Neel Scarsdale Ninad M. Walavalkar William A. Buchwald Gordon D. Ginder David C. Williams Jr. 《The Journal of biological chemistry》2014,289(3):1294-1302
Although highly homologous to other methylcytosine-binding domain (MBD) proteins, MBD3 does not selectively bind methylated DNA, and thus the functional role of MBD3 remains in question. To explore the structural basis of its binding properties and potential function, we characterized the solution structure and binding distribution of the MBD3 MBD on hydroxymethylated, methylated, and unmethylated DNA. The overall fold of this domain is very similar to other MBDs, yet a key loop involved in DNA binding is more disordered than previously observed. Specific recognition of methylated DNA constrains the structure of this loop and results in large chemical shift changes in NMR spectra. Based on these spectral changes, we show that MBD3 preferentially localizes to methylated and, to a lesser degree, unmethylated cytosine-guanosine dinucleotides (CpGs), yet does not distinguish between hydroxymethylated and unmethylated sites. Measuring residual dipolar couplings for the different bound states clearly shows that the MBD3 structure does not change between methylation-specific and nonspecific binding modes. Furthermore, residual dipolar couplings measured for MBD3 bound to methylated DNA can be described by a linear combination of those for the methylation and nonspecific binding modes, confirming the preferential localization to methylated sites. The highly homologous MBD2 protein shows similar but much stronger localization to methylated as well as unmethylated CpGs. Together, these data establish the structural basis for the relative distribution of MBD2 and MBD3 on genomic DNA and their observed occupancy at active and inactive CpG-rich promoters. 相似文献
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