This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The Mixed-Lineage Leukaemia (MLL) gene is a frequent target for recurrent specific chromosomal translocations that result in fusions between MLL and many different genes. Fusions with MLL are often found in human leukaemia. The MLL protein is a SET domain-dependent histone H3 lysine 4 (K4)-specific methyltransferase that exists as part of a multiprotein complex of at least 29 proteins. The mechanisms by which wild type or oncogenic MLL fusion proteins are recruited to specific target genes in chromatin are poorly understood. In the N-terminal region of MLL a cysteine-rich CXXC domain is present that possesses two CGXCXXC repeats. This CXXC domain is also present in a number of other chromatin-associated proteins. The CXXC domain is retained in all MLL fusion proteins and is essential for target gene recognition, transactivation and myeloid transformation. The CXXC domain in MLL and in several other proteins, has been shown to bind to nonmethyl-CpG dinucleotides. Cytosine methylation is the major epigenetic DNA modification in eukaryotes, and in vertebrates is found almost exclusively in a 5' CpG context where it functions to maintain stable gene silencing through mitotic cell divisions. DNA methylated at the cytosine of CpG dinucleotides is found in transcriptionally inactive genes, whereas actively expressed genes are generally hypomethylated. The CXXC domain may play an important role in directing MLL and oncogenic MLL fusion proteins to transcriptionally active genes. In order to determine the mechanism of binding to nonmethyl-CpG containing DNA, we would like to determine the 3D atomic structure of the CXXC domain of human MLL in both the apo and DNA bound forms. These studies would provide a structural basis for the development of novel therapeutics for the treatment of MLL-related leukaemias.
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