期刊
EMBO JOURNAL
卷 25, 期 19, 页码 4503-4512出版社
WILEY
DOI: 10.1038/sj.emboj.7601340
关键词
chromatin; CpG dinucleotide; CXXC domain; methylation; mixed lineage leukaemia
资金
- MRC [MC_U105161083, MC_U105459896] Funding Source: UKRI
- Medical Research Council [MC_U105459896, MC_U105161083] Funding Source: researchfish
- Medical Research Council [MC_U105459896, MC_U105161083] Funding Source: Medline
Methylation of CpG dinucleotides is the major epigenetic modification of mammalian genomes, critical for regulating chromatin structure and gene activity. The mixed-lineage leukaemia (MLL) CXXC domain selectively binds nonmethyl-CpG DNA, and is required for transformation by MLL fusion proteins that commonly arise from recurrent chromosomal translocations in infant and secondary treatment-related acute leukaemias. To elucidate the molecular basis of nonmethyl-CpG DNA recognition, we determined the structure of the human MLL CXXC domain by multidimensional NMR spectroscopy. The CXXC domain has a novel fold in which two zinc ions are each coordinated tetrahedrally by four conserved cysteine ligands provided by two CGXCXXC motifs and two distal cysteine residues. We have identified the CXXC domain DNA binding interface by means of chemical shift perturbation analysis, cross-saturation transfer and site-directed mutagenesis. In particular, we have shown that residues in an extended surface loop are in close contact with the DNA. These data provide a template for the design of specifically targeted therapeutics for poor prognosis MLL-associated leukaemias.
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