A Novel Domain That Recruits the Polycomb Group

Polycomb 集团招募的新领域

基本信息

批准号：
8651300
负责人：
Sarah Junco Wong
金额：
$ 2.42万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8651300
关键词：
Ankyrin Repeat BCL6 gene Binding Binding Sites Chromosomal translocation Complex Coupling Data Development Disease Drosophila genus Drosophila melanogaster Drug Targeting Epigenetic Process Evolution F Box Domain Genes Genetic Transcription Goals Hematopoietic Neoplasms Histones Human Laboratories Leucine-Rich Repeat Malignant Neoplasms Mammals Mediating Methods Modeling Modification Molecular Mutation N-terminal Nuclear Magnetic Resonance Orthologous Gene Polycomb Protein Deregulation Proteins Recruitment Activity Relative (related person)Repression Research Role Selenomethionine Solubility Solutions Structure Syndrome Testing Ubiquitin base demethylation histone modification novel paralogous gene prevent protein complex protein structure public health relevance research study therapeutic target tumor progression yeast two hybrid system

Ankyrin Repeat BCL6 gene Binding Binding Sites Chromosomal translocation Complex Coupling Data Development Disease Drosophila genus Drosophila melanogaster Drug Targeting Epigenetic Process Evolution F Box Domain Genes Genetic Transcription Goals Hematopoietic Neoplasms Histones Human Laboratories Leucine-Rich Repeat Malignant Neoplasms Mammals Mediating Methods Modeling Modification Molecular Mutation N-terminal Nuclear Magnetic Resonance Orthologous Gene Polycomb Protein Deregulation Proteins Recruitment Activity Relative (related person)Repression Research Role Selenomethionine Solubility Solutions Structure Syndrome Testing Ubiquitin base demethylation histone modification novel paralogous gene prevent protein complex protein structure public health relevance research study therapeutic target tumor progression yeast two hybrid system

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项目摘要

DESCRIPTION (provided by applicant): A novel domain that recruits the Polycomb Group Polycomb group (PcG) proteins were first discovered for their silencing function of the homeotic (Hox) genes in Drosophila melanogaster. These proteins form transcriptionally repressive complexes that mediate epigenetic modifications of histones. Much is unknown about these complexes, including how they are recruited to specific genes and how H2A ubiquitylation mediates repression. Current speculation is that H2A ubiquitylation either recruits repressive complexes or prevents recruitment of complexes needed for transcription. The importance of these epigenetic modifications is reflected by the observations that misregulation of PcG proteins have been associated with many malignancies. Aberrant expression, mutations and chromosomal translocations of PcG proteins have been observed in a wide variety of cancers. The number of genes encoding PcG proteins in mammals has expanded relative to Drosophila suggesting a greater complexity of function and molecular mechanism. Humans have six orthologs of the Drosophila PcG protein Psc: NSPC1, PCGF3, PCGF5, BMI-1, MEL18, and MBLR, all of which contain a ubiquitin (Ub) fold domain for interaction with other proteins. Binding studies suggest the existence of distinct functional classes of Ub folds within the PcG. Our hypothesis is that the Ub fold domains of Psc orthologs may have evolved to bind different proteins to form distinct repressive complexes. In the BCOR complex, the NSPC1 Ub fold binds BCL6 Co-Repressor (BCOR), which in turn binds F-box and Leucine Rich Repeat 10 (FBXL10), a histone demethylase thus coupling PcG repression with histone demethylation. Mutation of BCOR in humans is responsible for the developmental syndrome OFCD and recent studies have implicated both BCOR and FBXL10 in hematopoietic malignancies. Our preliminary studies have shown that the binding region of BCOR to NSPC1 contains a novel fold, which may provide information as to how these paralogs form distinct repressive complexes. Other data hints that the minimal binding region of FBXL10 on BCOR may overlap with that of NSPC1. The goal is to determine the combined structure of the interacting domains of the NSPC1, BCOR, and FBXL10 triple complex. Solving this structure will be important for elucidating the differences in binding partners that are bound by the ubiquitin fold containing proteins and possibly identifying novel drug targets.

描述（由申请人提供）：募集Polycomb组PolyComb组（PCG）蛋白的新型领域首先是在果蝇中杂种基因的沉默（HOX）基因的沉默功能而发现的。这些蛋白质形成了介导组蛋白表观遗传修饰的转录抑制复合物。对于这些复合物，包括如何招募到特定基因以及H2A泛素化介导抑制作用，这是未知的。当前的猜测是，H2A泛素化可以募集抑制性复合物或阻止转录所需的复合物的募集。这些表观遗传修饰的重要性反映了观察到PCG蛋白与许多恶性肿瘤相关的错误调节。在多种癌症中观察到了PCG蛋白的异常表达，突变和染色体易位。编码哺乳动物中PCG蛋白的基因数量相对于果蝇的扩展，表明功能和分子机制的复杂性更高。人类有六个果蝇PCG蛋白PSC的直系同源物：NSPC1，PCGF3，PCGF5，BMI-1，MEL18和MBLR，所有这些都包含泛素（UB）折叠域，以与其他蛋白质相互作用。结合研究表明，PCG中存在UB折叠的不同功能类别。我们的假设是，PSC直系同源物的UB折叠结构域可能已经演变为结合不同的蛋白质以形成不同的抑制性复合物。在BCOR络合物中，NSPC1 UB折叠结合了Bcl6共抑制剂（BCOR），后者又结合了F-box和富含亮氨酸的重复10（FBXL10），这是组蛋白脱甲基酶，从而将PCG抑制与组蛋白脱甲基偶联。 BCOR在人类中的突变导致了OFCD的发育综合征，最近的研究涉及BCOR和FBXL10在造血恶性肿瘤中。我们的初步研究表明，BCOR与NSPC1的结合区域包含一个新颖的折叠，可以提供有关这些旁系同源物如何形成不同抑制性复合物的信息。其他数据暗示，BCOR上FBXL10的最小结合区域可能与NSPC1的结合区域重叠。目标是确定NSPC1，BCOR和FBXL10三重配合物的相互作用域的组合结构。解决这种结构对于阐明由含有蛋白质的泛素折叠和可能鉴定出新型药物靶标的泛素折叠的结合伴侣的差异很重要。