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Drosophila MCM10 in DNA replication and Heterochromatin formation

果蝇 MCM10 在 DNA 复制和异染色质形成中的作用

基本信息

批准号：
7879828
负责人：
TIMOTHY W CHRISTENSEN
金额：
$ 21.53万
依托单位：
EAST CAROLINA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7879828
关键词：
Address Alleles Base Sequence Biochemical Biological Assay Biology Brain Bromodeoxyuridine Cancer Biology Cancerous Cell Cycle Cell division Cells Chorion Chromatin Chromosomes Collection DNA DNA Replication Factor DNA biosynthesis Defect Diagnosis Diagnostic Dimensions Disease Drosophila genus Drosophila melanogaster Embryo Epigenetic Process Event Failure Gene Amplification Gene Expression Genetic Genome Growth Heterochromatin Human Lead Link Maintenance Malignant Neoplasms Modification Morphology Mutation Normal tissue morphology Nucleotides Nurses Ovary Phenotype Phosphorus Physical condensation Play Point Mutation Process Proteins Regulation Reporter Role System Technology Testing Tissue Differentiation Tissues Yeast Model System cancer cell cancer therapy cell growth developmental genetics effective therapy human disease mutant public health relevance spelling synchronous cell division tool yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): Cancer consists of a multitude of specific disease states, all of which share in common: unregulated growth, failure to differentiate, and defects in chromosome biology. Defects in chromosomal biology and unregulated growth of cells are often the result of mis-regulation and/or mutations of the DNA replication machinery. However, it is becoming increasingly apparent that cancer is not driven solely by classical mutation but is also initiated and maintained by epigenetic changes. Epigenetic changes are alterations not associated with the nucleotide sequence of the genome but rather modifications of the nucleotides and DNA associated proteins that result in altered expression of genes. This altered expression is often the result of the formation of tightly packed DNA in the form of heterochromatin. Taken separately, both DNA replication and heterochromatin formation are important aspects of cancer biology. Understanding these two processes has been important for our understanding and treatment of cancer. Understanding how these two processes are linked promises to add a new and useful dimension to our ongoing efforts to confront cancer. The core aim of this proposal is to begin spell out how DNA replication and heterochromatin formation are linked through the study of Drosophila Mcm10. Study of this proteins on this level we allow us to begin to understand the network of interactions between DNA replication and heterochromatin formation. Using newly available technologies we will identify multiple alleles of MCM10 which will enable the separation of MCM10 function with respect to DNA replication and chromatin biology. Parsing these roles apart has the potential to lead to new therapies and diagnostics in treating cancer. Toward this end we propose to use the tractable genetic system Drosophila melanogaster to explore the following hypothesis: The Drosophila DNA replication factor MCM10 has separable functions in DNA replication and chromatin dynamics. We will address this hypothesis through the following specific aims: 1. Identify and characterize mutants in Drosophila MCM10 2. Assay MCM10 alleles for impacts on DNA replication 3. Assay MCM10 alleles for impacts on chromosome morphology and cell cycle 4. Assay the consequences of the MCM10 alleles on heterochromatin formation 5. Determine the consequences of these MCM10 alleles on interactions with other proteins PUBLIC HEALTH RELEVANCE: Understanding the link between how DNA is packaged appropriately and how DNA is copied will provide a broader understanding of how cancer develops in humans. Revealing the details of how these essential processes are linked will inform the diagnosis and treatment of cancer.

描述（由申请人提供）：癌症由多种特定的疾病状态组成，所有这些疾病状态都有一个共同点：生长不受调节、无法分化和染色体生物学缺陷。染色体生物学缺陷和细胞生长不受调节通常是DNA复制机制的错误调节和/或突变的结果。然而，越来越明显的是，癌症不仅仅是由经典突变驱动的，而且还由表观遗传变化引发和维持。表观遗传变化是与基因组的核苷酸序列无关的改变，而是导致基因表达改变的核苷酸和DNA相关蛋白质的修饰。这种改变的表达通常是以异染色质形式形成紧密包装的DNA的结果。单独来看，DNA复制和异染色质形成都是癌症生物学的重要方面。了解这两个过程对于我们理解和治疗癌症非常重要。了解这两个过程是如何联系在一起的，有望为我们正在进行的对抗癌症的努力增加一个新的和有用的层面。这项提案的核心目标是通过对果蝇Mcm 10的研究，开始阐明DNA复制和异染色质形成是如何联系在一起的。在这个水平上研究这种蛋白质，我们可以开始理解DNA复制和异染色质形成之间的相互作用网络。使用新的可用技术，我们将确定多个等位基因的MCM 10，这将使分离的MCM 10功能方面的DNA复制和染色质生物学。将这些角色分开分析有可能导致治疗癌症的新疗法和诊断。为此，我们建议使用易处理的遗传系统果蝇黑腹果蝇探讨以下假设：果蝇DNA复制因子MCM 10具有可分离的功能，在DNA复制和染色质动力学。我们将通过以下具体目标来解决这个假设：1。鉴定和表征果蝇MCM 10 2中的突变体。测定MCM 10等位基因对DNA复制的影响3.测定MCM 10等位基因对染色体形态和细胞周期的影响4。分析MCM 10等位基因对异染色质形成的影响5.确定这些MCM 10等位基因对与其他蛋白质相互作用的影响公共卫生关系：了解DNA如何被适当包装和DNA如何被复制之间的联系，将有助于更广泛地了解癌症如何在人类中发展。揭示这些基本过程如何联系的细节将为癌症的诊断和治疗提供信息。