MIXED LINEAGE LEUKEMIA (MLL) METHYLTRANSFERASE CXXC DNA BINDING DOMAIN

混合谱系白血病 (MLL) 甲基转移酶 CXXC DNA 结合域

• 批准号: 7602306
• 负责人: STEVEN C. ALMO
• 金额: $ 0.7万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7602306
• 关键词: Binding; Cell division; Chimeric Proteins; Chromatin; Chromosomal translocation; Computer Retrieval of Information on Scientific Projects Database; CpG dinucleotide; Cysteine; Cytosine; DNA; DNA Binding; DNA Modification Process; Development; Epigenetic Process; Eukaryota; Eukaryotic Cell; Funding; Gene Silencing; Gene Targeting; Genes; Grant; Histone H3; Human; Institution; Lysine; MLL gene; Methylation; Methyltransferase; Mitotic; Multiprotein Complexes; Myelogenous; Myeloid-Lymphoid Leukemia Protein; N-terminal; Numbers; Oncogenic; Play; Proteins; Recruitment Activity; Recurrence; Research; Research Personnel; Resources; Role; SET Domain; Source; Structure; Transactivation; United States National Institutes of Health; Vertebrates; base; leukemia; novel therapeutics

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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 混合谱系白血病（MLL）基因是导致MLL与许多不同基因之间融合的复发性特异性染色体易位的常见靶标。 与MLL的融合常见于人类白血病。 MLL蛋白是SET结构域依赖性组蛋白H3赖氨酸4（K4）特异性甲基转移酶，其作为至少29种蛋白质的多蛋白复合物的一部分存在。 野生型或致癌MLL融合蛋白被募集到染色质中的特定靶基因的机制知之甚少。 在MLL的N-末端区域中存在富含半胱氨酸的CXXC结构域，其具有两个CGXCXXC重复。 该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，并且对于靶基因识别、反式激活和骨髓转化是必需的。 MLL和其他几种蛋白质中的CXXC结构域已显示与非甲基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，并且在脊椎动物中几乎仅在5' CpG背景下发现，其中其用于通过有丝分裂细胞分裂维持稳定的基因沉默。在转录失活基因中发现CpG二核苷酸胞嘧啶甲基化的DNA，而活跃表达的基因通常甲基化不足。CXXC结构域可能在指导MLL和致癌MLL融合蛋白转录活性基因中起重要作用。 为了确定与含有非甲基CpG的DNA结合的机制，我们想要确定人MLL的CXXC结构域在载脂蛋白和DNA结合形式中的3D原子结构。 这些研究将为开发用于治疗MLL相关白血病的新疗法提供结构基础。