Recognition of 5-hydroxymethylcytosine by the Uhrf1 SRA domain

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...

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Published inPloS one Vol. 6; no. 6; p. e21306
Main Authors Frauer, Carina, Hoffmann, Thomas, Bultmann, Sebastian, Casa, Valentina, Cardoso, M Cristina, Antes, Iris, Leonhardt, Heinrich
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 22.06.2011
Public Library of Science (PLoS)
Subjects
5-Methylcytosine - metabolism
Algorithms
Binding Sites
Biology
CCAAT-Enhancer-Binding Proteins - chemistry
CCAAT-Enhancer-Binding Proteins - metabolism
Cellular proteins
Competition
Computer Science
CpG islands
CpG Islands - genetics
Crystal structure
Cytosine
Cytosine - analogs & derivatives
Cytosine - metabolism
Deoxyribonucleic acid
DNA
DNA - chemistry
DNA - metabolism
DNA methylation
Epigenetic inheritance
Epigenetics
Gene expression
HEK293 Cells
Humans
Hydrogen
Hydrogen Bonding
Hydrogen bonds
Hydroxides
Hydroxyl groups
Life sciences
Mammals
MeCP2 protein
Methyl-CpG binding protein
Methylation
Molecular dynamics
Molecular Dynamics Simulation
Molecular structure
Physical chemistry
Physics
Protein Binding
Protein Structure, Tertiary
Proteins
Pyrimidines
Stem cells
Studies
Substrates
Thermodynamics
Germany
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Summary: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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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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0021306