Recognition of multivalent histone states associated with heterochromatin by UHRF1 protein |
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Authors: | Nady Nataliya Lemak Alexander Walker John R Avvakumov George V Kareta Michael S Achour Mayada Xue Sheng Duan Shili Allali-Hassani Abdellah Zuo Xiaobing Wang Yun-Xing Bronner Christian Chédin Frédéric Arrowsmith Cheryl H Dhe-Paganon Sirano |
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Affiliation: | Ontario Cancer Institute, and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada. |
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Abstract: | 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. |
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Keywords: | Epigenetics Gene Silencing NMR Protein Structure X-ray Crystallography Histone PTMs Tudor Domain |
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