MIXED LINEAGE LEUKEMIA (MLL) METHYLTRANSFERASE CXXC DNA BINDING DOMAIN

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 混合系白血病(MLL)基因是反复发生的特定染色体易位的常见靶点，这种易位导致MLL与许多不同基因之间的融合。与MLL的融合经常在人类白血病中发现。MLL蛋白是一种组蛋白H3赖氨酸4(K4)特异性甲基转移酶，它是由至少29种蛋白质组成的多蛋白复合体的一部分。野生型或致癌的MLL融合蛋白被招募到染色质中特定的靶基因的机制尚不清楚。在MLL的N-末端区域存在一个富含半胱氨酸的CXXC结构域，它具有两个CGXCXXC重复序列。这个CXXC结构域也存在于许多其他染色质相关蛋白中。CXXC结构域保留在所有MLL融合蛋白中，是靶基因识别、反式激活和髓系转化所必需的。MLL和其他几种蛋白质中的CXXC结构域已被证明与非甲基CpG二核苷酸结合。胞嘧啶甲基化是真核生物中主要的表观遗传DNA修饰，在脊椎动物中几乎只在5‘CpG环境中发现，在这种环境中，胞嘧啶甲基化通过有丝分裂细胞分裂来维持稳定的基因沉默。在CpG二核苷酸胞嘧啶甲基化的DNA在转录不活跃的基因中被发现，而活跃表达的基因通常是低甲基化的。CXXC结构域可能在引导MLL和致癌MLL融合蛋白转录活性基因方面发挥重要作用。为了确定与含有非甲基CpG的DNA结合的机制，我们想要测定人MLL在载脂蛋白和DNA结合形式下CXXC结构域的三维原子结构。这些研究将为开发治疗MLL相关白血病的新疗法提供结构基础。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for 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.