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Recognition of multivalent histone states associated with heterochromatin by UHRF1 protein.

http://www.ncbi.nlm.nih.gov/pubmed/21489993

Histone modifications and DNA methylation represent two layers of heritable epigenetic information that regulate eukaryotic chromatin structure and gene activity. UHRF1 is a unique factor that bridges these two layers; it is required for maintenance DNA methylation at hemimethylated CpG sites, which are specifically recognized through its SRA domain and also interacts with histone H3 trimethylated on lysine 9 (H3K9me3) in an unspecified manner. Here we show that UHRF1 contains a tandem Tudor domain (TTD) that recognizes H3 tail peptides with the heterochromatin-associated modification state of trimethylated lysine 9 and unmodified lysine 4 (H3K4me0/K9me3). Solution NMR and crystallographic data reveal the TTD simultaneously recognizes H3K9me3 through a conserved aromatic cage in the first Tudor subdomain and unmodified H3K4 within a groove between the tandem subdomains. The subdomains undergo a conformational adjustment upon peptide binding, distinct from previously reported mechanisms for dual histone mark recognition. Mutant UHRF1 protein deficient for H3K4me0/K9me3 binding shows altered localization to heterochromatic chromocenters and fails to reduce expression of a target gene, p16(INK4A), when overexpressed. Our results demonstrate a novel recognition mechanism for the combinatorial readout of histone modification states associated with gene silencing and add to the growing evidence for coordination of, and cross-talk between, the modification states of H3K4 and H3K9 in regulation of gene expression.

Pubmed ID: 21489993 RIS Download

Mesh terms: Animals | Binding Sites | CCAAT-Enhancer-Binding Proteins | CpG Islands | Crystallography, X-Ray | Cyclin-Dependent Kinase Inhibitor p16 | DNA Methylation | Gene Expression Regulation | Heterochromatin | Histones | Humans | Mice | Mice, Knockout | Nuclear Magnetic Resonance, Biomolecular | Protein Processing, Post-Translational | Protein Structure, Tertiary

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Associated grants

  • Agency: Canadian Institutes of Health Research, Id:
  • Agency: Wellcome Trust, Id:

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