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Initiation of SV40 DNA Replication and Its Regulation

SV40 DNA复制的启动及其调控

基本信息

批准号：
6844339
负责人：
PETER Augustus BULLOCK
金额：
$ 30.91万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-01-01 至 2006-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6844339
关键词：
DNA replication DNA replication origin nucleic acid sequence simian virus 40 tissue /cell culture virus genetics virus protein virus replication

项目摘要

DESCRIPTION (provided by applicant): Many DNA tumor viruses encode "initiators" proteins that site specifically bind to viral origins of DNA replication. Upon binding to their respective origins, the initiators assemble into DNA helicases that are capable of melting duplex DNA. Initiators also recruit cellular proteins required for synthesis of nascent DNA. We are attempting to understand these processes by characterizing in depth an initiator encoded by Simian Virus 40, termed T-antigen (T-ag). Using the Simian Virus 40 system and simple band shift experiments, a fundamental question in biology will be addressed: "how does the cell cycle machinery control the assembly of initiators on viral origins of replication?" Recent experiments with T-ag derived peptides, whose ability to bind to DNA is regulated by phosphorylation of Thr 124, are providing significant insights into this process. Experiments are proposed to determine if similar mechanisms are operating in the context of T-ag. Related aspects of T-ag assembly and regulation will be considered, such as locating a site on T-ag whose interactions with the flanking sequences in the core origin is necessary for T-ag binding. Collectively, these studies will provide information that may allow us to solve the mechanism of DNA unwinding. Once the SV40 origin is unwound, the pol alpha-primase complex initiates the synthesis of nascent DNA strands. Exactly what sequences constitute the initiation sites for the pol alpha-primase complex is the topic of an additional series of experiments. Given that many basic processes are conserved throughout evolution, we are confident that the information we obtain from these studies will be pertinent to the initiation of DNA replication at other viral origins of replication. Furthermore, they may help us to understand how the cell cycle machinery controls initiation events at cellular origins. Given that uncontrolled DNA replication is thought to be a component of many diseases, including cancer, it is very important to understand how DNA replication is initiated and how it is controlled.

描述（由申请人提供）：许多DNA肿瘤病毒编码“启动子” 与病毒DNA复制起点位点特异性结合的蛋白质。后结合到它们各自的起点，引发剂组装成DNA解旋酶能够解链双链体DNA发起人还招募细胞合成新生DNA所需的蛋白质。我们试图了解通过深入研究猿猴病毒编码的启动子， 40，称为T抗原（T-ag）。使用猿猴病毒40系统和简单条带转移实验，生物学中的一个基本问题将得到解决：“如何细胞周期机制是否控制着病毒启动子的组装复制源？“最近对T-ag衍生肽的实验，与DNA结合的能力受Thr 124的磷酸化调节，为这一过程提供了重要的见解。实验被提议为确定类似的机制是否在T-ag的背景下运行。相关将考虑T-ag组装和监管方面的问题，例如定位一个 T-ag上与核心起源中的侧翼序列相互作用的位点是T-ag结合所必需的。这些研究将提供这些信息可以帮助我们解决DNA解旋的机制。一旦 SV 40起源解绕，pol α-引发酶复合物启动合成新生的DNA链到底是什么序列构成了对于聚合酶α-引发酶复合物是一个额外的系列的主题，实验由于许多基本过程都是保守的，我们相信，我们从这些研究中获得的信息将与其他病毒起点的DNA复制起始有关复制。此外，它们还可以帮助我们了解细胞周期是如何机械控制细胞起源的起始事件。鉴于不受控制的DNA复制被认为是许多疾病的组成部分，包括癌症，了解DNA复制是如何它是如何启动的，以及如何控制的。