DNA replication and cytokinesis

DNA复制和胞质分裂

基本信息

批准号：
8082394
负责人：
IGOR N CHESNOKOV
金额：
$ 27.84万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8082394
关键词：
Address Aging Behavior Binding Cell Cycle Cell Cycle Progression Cell physiology Cells Chromosomes Complex Cytokinesis DNA DNA Binding DNA biosynthesis DNA replication origin Data Dimerization Disease Drosophila genus Employee Strikes Eukaryota Event Evolution Filament Genetic Genetic Transcription Goals Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Human In Vitro Injury Lead Learning Malignant Neoplasms Mammals Membrane Methods Mitotic Modeling Molecular Molecular Models N-terminal Peptide Initiation Factors Play Positioning Attribute Process Protein Complex Subunit Proteins Regulation Replication Initiation Replication Origin Research Role Signal Pathway Structure Testing Time Transcription Factor TFIIB Ursidae Family X-Ray Crystallography base cancer therapy dimer in vivo insight member molecular modeling origin recognition complex programs promoter protein protein interaction research study therapy design three dimensional structure

项目摘要

DESCRIPTION (provided by applicant): The Origin Recognition Complex (ORC), heteromeric six-subunit protein complex, is essential for DNA replication. ORC's functions also extend beyond DNA replication. In our preliminary studies, we found that the Drosophila smallest ORC subunit, Orc6, is important for DNA binding and DNA replication but also has a function in cytokinesis through the interaction with septin protein Pnut. Based on these observations we hypothesize that Orc6 is a multifunctional protein. Orc6 might be involved in a signaling pathway that coordinates many processes of the cell division cycle, such as chromosome duplication and cytokinesis. We hypothesize that Orc6, which bears a structural homology with transcription factor, TFIIB, is essential for targeting of ORC to the origins in Drosophila cells and for the formation of pre- replicative complex. The function of Orc6 in cytokinesis is achieved through the regulation of septin complex activities. To test these hypotheses we plan to analyze at the molecular, cellular and genetic levels the functions and activities of Orc6 and its role in cell cycle. Specifically we will 1) determine the three-dimensional structure of Orc6; 2) detertmine functions of Orc6 in DNA binding and DNA replication; and 3) elucidate the role of Orc6 in regulation of septin complex functions. Because ORC is conserved in evolution, what we learn about its functions in Drosophila will be valuable to our understanding of ORC's functions in other eukaryotes. A better understanding of how ORC functions in Drosophila will provide insights into ORC's behavior in mammals and provide clues as to how its misregulation leads to cancer. PUBLIC HEALTH RELEVANCE: Project narrative. The goal of our proposal is to define the role of Origin Recognition Complex (ORC) during the cell cycle in eukaryotes. Because ORC is conserved in evolution, what we learn about its functions will provide insights as to how its misregulation leads to cancer. An understanding of the molecular events involved in the initiation of replication and cell cycle progression will provide a basis for ultimately controlling these processes.

描述（由申请人提供）：原始识别复合物（ORC），杂体六亚基蛋白复合物，对于DNA复制至关重要。兽人的功能还超出了DNA复制。在我们的初步研究中，我们发现果蝇最小的兽人亚基ORC6对于DNA结合和DNA复制很重要，但通过与Septin Protin Pnut的相互作用，在细胞因子中也具有功能。基于这些观察结果，我们假设ORC6是一种多功能蛋白。 ORC6可能参与了协调细胞分裂周期许多过程的信号通路，例如染色体复制和细胞因子。我们假设具有带有转录因子TFIIB的结构同源性的ORC6对于将ORC靶向果蝇细胞中的起源以及形成presplicative复合物是必不可少的。 ORC6在细胞因子中的功能是通过调节SEPTIN复合活性来实现的。为了检验这些假设，我们计划在分子，细胞和遗传水平上分析ORC6的功能和活性及其在细胞周期中的作用。具体而言，我们将1）确定ORC6的三维结构； 2）ORC6在DNA结合和DNA复制中的介质功能； 3）阐明了ORC6在Septin复合函数调节中的作用。因为兽人在进化中是保守的，所以我们对果蝇中其功能的了解将对我们对其他真核生物中兽人功能的理解很有价值。对果蝇中ORC的功能如何更好地理解将提供对哺乳动物中ORC行为的见解，并提供有关其不正调如何导致癌症的线索。公共卫生相关性：项目叙述。我们建议的目的是在真核生物中的细胞周期中定义原点识别复合物（ORC）的作用。因为兽人在进化中是保守的，所以我们了解其功能的知识将提供有关其不正调如何导致癌症的见解。对复制和细胞周期进程涉及的分子事件的理解将为最终控制这些过程提供基础。