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      Recognition of 5-Hydroxymethylcytosine by the Uhrf1 SRA Domain

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          Abstract

          Recent discovery of 5-hydroxymethylcytosine (5hmC) in genomic DNA raises the question how this sixth base is recognized by cellular proteins. In contrast to the methyl-CpG binding domain (MBD) of MeCP2, we found that the SRA domain of Uhrf1, an essential factor in DNA maintenance methylation, binds 5hmC and 5-methylcytosine containing substrates with similar affinity. Based on the co-crystal structure, we performed molecular dynamics simulations of the SRA:DNA complex with the flipped cytosine base carrying either of these epigenetic modifications. Our data indicate that the SRA binding pocket can accommodate 5hmC and stabilizes the flipped base by hydrogen bond formation with the hydroxyl group.

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          Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain.

          Cytosine methylation is the major covalent modification of mammalian genomic DNA and plays important roles in transcriptional regulation. The molecular mechanism underlying the enzymatic removal of this epigenetic mark, however, remains elusive. Here, we show that 5-methylcytosine (5mC) hydroxylase TET1, by converting 5mCs to 5-hydroxymethylcytosines (5hmCs), promotes DNA demethylation in mammalian cells through a process that requires the base excision repair pathway. Though expression of the 12 known human DNA glycosylases individually did not enhance removal of 5hmCs in mammalian cells, demethylation of both exogenously introduced and endogenous 5hmCs is promoted by the AID (activation-induced deaminase)/APOBEC (apolipoprotein B mRNA-editing enzyme complex) family of cytidine deaminases. Furthermore, Tet1 and Apobec1 are involved in neuronal activity-induced, region-specific, active DNA demethylation and subsequent gene expression in the dentate gyrus of the adult mouse brain in vivo. Our study suggests a TET1-induced oxidation-deamination mechanism for active DNA demethylation in mammals. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Tissue Distribution of 5-Hydroxymethylcytosine and Search for Active Demethylation Intermediates

            5–Hydroxymethylcytosine (hmC) was recently detected as the sixth base in mammalian tissue at so far controversial levels. The function of the modified base is currently unknown, but it is certain that the base is generated from 5-methylcytosine (mC). This fuels the hypothesis that it represents an intermediate of an active demethylation process, which could involve further oxidation of the hydroxymethyl group to a formyl or carboxyl group followed by either deformylation or decarboxylation. Here, we use an ultra-sensitive and accurate isotope based LC-MS method to precisely determine the levels of hmC in various mouse tissues and we searched for 5–formylcytosine (fC), 5-carboxylcytosine (caC), and 5–hydroxymethyluracil (hmU) as putative active demethylation intermediates. Our data suggest that an active oxidative mC demethylation pathway is unlikely to occur. Additionally, we show using HPLC-MS analysis and immunohistochemistry that hmC is present in all tissues and cell types with highest concentrations in neuronal cells of the CNS.
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              Development and current status of the CHARMM force field for nucleic acids.

              The CHARMM27 all-atom force field for nucleic acids represents a highly optimized model for investigations of nucleic acids via empirical force field calculations. The force field satisfactorily treats the A, B, and Z forms of DNA as well as RNA, and it also useful for nucleosides and nucleotides. In addition, it is compatible with the CHARMM force fields for proteins and lipids, allowing for simulation studies of heterogeneous systems. Copyright 2001 John Wiley & Sons, Inc. Biopolymers (Nucleic Acid Sci) 56: 257-265, 2001
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                22 June 2011
                : 6
                : 6
                : e21306
                Affiliations
                [1 ]Department of Biology II, Ludwig Maximilians University Munich, Planegg-Martinsried, Germany
                [2 ]Department of Life Sciences, Technical University Munich, Freising-Weihenstephan, Germany
                [3 ]Department of Biology, Technical University Darmstadt, Darmstadt, Germany
                [4 ]Center for Integrated Protein Science Munich (CIPSM), Munich, Germany
                New England Biolabs, Inc., United States of America
                Author notes

                Conceived and designed the experiments: CF HL IA MCC TH. Performed the experiments: CF TH. Analyzed the data: CF HL IA TH. Wrote the paper: CF HL IA. Performed initial experiments: SB VC.

                Article
                PONE-D-11-05080
                10.1371/journal.pone.0021306
                3120858
                21731699
                ea7fc3a3-23a2-4604-8315-a8bafa860e25
                Frauer et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 18 March 2011
                : 25 May 2011
                Page count
                Pages: 8
                Categories
                Research Article
                Biology
                Biochemistry
                Enzymes
                Enzyme Structure
                Nucleic Acids
                DNA
                Proteins
                DNA-binding proteins
                Protein Interactions
                Protein Structure
                Biochemistry Simulations
                Computer Science
                Computer Modeling
                Computerized Simulations

                Uncategorized
                Uncategorized

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