The structural basis for selective binding of non-methylated CpG islands by the CFP1 CXXC domain

Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
Nature Communications (Impact Factor: 11.47). 03/2011; 2(1):227. DOI: 10.1038/ncomms1237
Source: PubMed


CFP1 is a CXXC domain-containing protein and an essential component of the SETD1 histone H3K4 methyltransferase complex. CXXC domain proteins direct different chromatin-modifying activities to various chromatin regions. Here, we report crystal structures of the CFP1 CXXC domain in complex with six different CpG DNA sequences. The crescent-shaped CFP1 CXXC domain is wedged into the major groove of the CpG DNA, distorting the B-form DNA, and interacts extensively with the major groove of the DNA. The structures elucidate the molecular mechanism of the non-methylated CpG-binding specificity of the CFP1 CXXC domain. The CpG motif is confined by a tripeptide located in a rigid loop, which only allows the accommodation of the non-methylated CpG dinucleotide. Furthermore, we demonstrate that CFP1 has a preference for a guanosine nucleotide following the CpG motif.

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Available from: Chao Xu, Sep 23, 2015
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    • "The efficiency of LOOXSTER depends on the differential G + C contents and DNA methylation rates between prokaryotic and eukaryotic DNA. The specific affinity of the LOOXSTER protein, a derivative of the human CXXC finger protein 1 (CFP1), for non-methylated CpG-dinucleotides is used to separate DNA containing non-methylated CpG-dinucleotides (bacterial DNA) from methylated CpG-dinucleotides (human DNA) (Xu et al., 2011). "
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    • "In the N-terminal part, the Tet proteins possess a CXXC domain, a binuclear Zn-chelating domain found in certain chromatin-associated proteins such as Dnmt1 methyltransferase, and other elements which mediate interactions with multiple components in the cell (Xu et al., 2011b; Zhang et al., 2010). Unlike the CXXC domains in other proteins, such as, DNMT1, myeloid/lymphoid or mixed-lineage leukemia (MLL) and CXXC finger protein 1 (CFP1, or CXXC1), which are known to bind unmethylated CpG dinucleotides (Cierpicki et al., 2010; Song et al., 2011b; Xu et al., 2011a), the function of this domain in Tet1 and Tet3 is largely unknown.Various group of workers have reported that CXXC domain of TET1 recognizes not only unmodified cytosine but also 5mC and 5-hmc, and it prefers to bind to regions in the genome of high CpG content (Xu et al., 2011b; Zhang et al., 2010). Depending on this feature, genomewide mapping of Tet1 binding by ChIP-seq approaches revealed its enrichment around transcription start sites (TSSs) in mouse ES cells (Figure 2) (Xu et al., 2011b; Williams et al., 2011; Wu et al., 2011). "
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    • "ing promoters and gene regulatory units in up to 70% of genes (Blackledge and Klose, 2011; Deaton and Bird, 2011; Gardiner-Garden and Frommer, 1987). Recent studies suggested that an unmethylated CpG dinucleotide was bound by a CxxC-zinc finger (CxxC-ZF) domain (Allen et al., 2006; Blackledge et al., 2010; Cierpicki et al., 2010; Lee et al., 2001; Song et al., 2011; Thomson et al., 2010; Voo et al., 2000) that was characterized by two CGXCXXC repeats and conserved cysteine residues that bound to two zinc ions (Long et al., 2013; Xu et al., 2011). It was reported that the CxxC-ZF domain was involved in targeting chromatin-modifying proteins to CpG islands, which may affect gene expression (Blackledge et al., 2010; Long et al., 2013; Smith and Shilatifard, 2010; Thomson et al., 2010). "
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