Structural Basis of Large T Helicase Function in SV40 DNA Replication
SV40 DNA 复制中大 T 解旋酶功能的结构基础
基本信息
- 批准号:8101029
- 负责人:
- 金额:$ 51.03万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-07-01 至 2014-06-30
- 项目状态:已结题
- 来源:
- 关键词:Abnormal CellAddressBindingBiochemicalBiochemistryBiologicalBiological AssayBiological ModelsCancer BiologyCarcinogensCell CycleCell physiologyCellsComplementComplexComputational BiologyComputing MethodologiesCouplingCrystallographyDNADNA BindingDNA PrimaseDNA biosynthesisDNA replication forkDNA replication originDataDevelopmentEukaryotaEukaryotic CellGoalsHumanHydrolysisIn VitroInterventionIrisKineticsKnowledgeLarge T AntigenLeadLiteratureMalignant NeoplasmsMammalian CellMethodsModelingMolecularMolecular BiologyMolecular MachinesMotionMutagenesisOncogenic VirusesPathway interactionsPhasePlayPolymerasePower strokeProcessProkaryotic CellsProteinsRecruitment ActivityReplication OriginResearchResolutionRestRoentgen RaysRoleSideSimian virus 40StructureStructure-Activity RelationshipSystemTopoisomeraseUrsidae FamilyViralViral ProteinsVirus Diseasesbasecell transformationdesignhelicaseinsightmeltingpublic health relevancereplication initiator proteinresponsesingle moleculeviral DNA
项目摘要
DESCRIPTION (provided by applicant): SV40 large T antigen (LT) is a potent carcinogen, and plays an essential role for SV40 DNA replication as the replicative helicase and replication initiator protein. SV40 replication serves as a model for eukaryotic DNA replication, as SV40 uses all the essential cellular replication proteins (primase, polymerase, PCNA, Topoisomerases, etc.), except for the helicase and cellular initiator proteins that consist of multiple initiator factors (such as Orc, Ctd1, Cdc6, MCM in eukaryotes, or DnaA/DnaC/DnaB in prokaryotes) to initiate DNA replication, i.e. marking the replication origin, recruiting helicase, melting origin, and activating helicase. For SV40 replication, LT alone fulfills essentially all the initiator functions and is the helicase for replication fork unwinding during elongation phase. The long-term goal of this research is to understand how LT functions as a helicase to coordinate the functions of the other replication proteins for DNA replication, as well as how LT transforms cells. Specific aims are designed to understand how LT hexameric and double hexameric helicase melt the origin DNA and unwinds dsDNA to initiate DNA replication. We plan to use mainly X-ray protein crystallography, assisted with EM and AFM, single molecule assay, computational method, molecular biology and functional biochemistry in vitro and in cells. The results from this research are expected to have potential impact on the field of DNA replication in eukaryotic cells and on cancer biology. PUBLIC HEALTH RELEVANCE: SV40 large T (LT) has remarkably diverse biological activities. Besides its ability to regulate many aspects of viral infection and cellular processes, LT in its hexameric and double hexameric forms is an efficient molecular machine that can melt dsDNA and unwind replication forks for DNA replication. LT is the only viral protein required for SV40 minichromosome DNA replication, all the rest proteins are from cellular replication machinery in mammalian cells. In this minichromosome replication, LT performs the functions of the cellular helicase MCM and several other initiator proteins for origin localization and melting. As a result, SV40 replication system has been serving as a model system for studying eukaryotic replication. The study of LT helicase mechanisms will have general implications for understanding other replicative helicases, especially for those from eukaryotic cells. We aim to understand the detailed molecular mechanisms of the helicase function of LT hexameric and double hexameric machine. The data generated from this research will provide valuable information about helicase function and DNA replication. This study bears high relevance to cancer biology.
描述(申请人提供):SV40大T抗原(LT)是一种强大的致癌物质,作为复制解旋酶和复制启动蛋白在SV40DNA复制中起着至关重要的作用。SV40复制是真核细胞DNA复制的模型,因为SV40使用除解旋酶和由多种启动子组成的细胞启动蛋白(如真核生物中的ORC、Ctd1、CDC6、MCM,或原核生物中的DNAA/DNAC/DNAB)外,所有必需的细胞复制蛋白(Primase、聚合酶、增殖细胞核抗原、拓扑异构酶等)来启动DNA复制,即标记复制起点、招募解旋酶、融化起点和激活解旋酶。对于SV40复制,单独的LT基本上完成了所有的启动子功能,并且是伸长阶段复制叉解旋的解旋酶。这项研究的长期目标是了解LT如何作为解旋酶来协调其他复制蛋白的DNA复制功能,以及LT如何转化细胞。特定的目的是为了了解LT六聚体和双六聚体螺旋酶是如何熔化原始DNA并解开dsDNA以启动DNA复制的。我们计划主要使用X射线蛋白质结晶学,辅以EM和AFM,单分子分析,计算方法,体外和细胞内的分子生物学和功能生物化学。这项研究的结果有望对真核细胞的DNA复制领域和癌症生物学产生潜在影响。公共卫生相关性:SV40大T(LT)具有非常多样化的生物活性。除了能够调节病毒感染和细胞过程的许多方面外,以六聚体和双六聚体形式存在的LT是一种高效的分子机器,可以熔化dsDNA并解开复制叉以进行DNA复制。它是SV40微小染色体DNA复制所需的唯一病毒蛋白,其余蛋白均来自哺乳动物细胞中的细胞复制机制。在这种微染色体复制中,LT发挥细胞解旋酶MCM和其他几种启动子蛋白的功能,用于起源定位和融化。因此,SV40复制系统一直是研究真核生物复制的模型系统。LT解旋酶机制的研究将对理解其他复制解旋酶,特别是来自真核细胞的解旋酶具有普遍意义。我们的目标是了解LT六聚体和双六聚体解旋酶功能的详细分子机制。这项研究产生的数据将提供关于解旋酶功能和DNA复制的有价值的信息。这项研究与癌症生物学有很高的相关性。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
XIAOJIANG S CHEN其他文献
XIAOJIANG S CHEN的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('XIAOJIANG S CHEN', 18)}}的其他基金
Structural Basis of APOBEC Functions and HIV Restriction
APOBEC 功能和 HIV 限制的结构基础
- 批准号:
10436802 - 财政年份:2009
- 资助金额:
$ 51.03万 - 项目类别:
Structural Basis of APOBEC Functions and Interactions with HIV-Vif
APOBEC 功能的结构基础以及与 HIV-Vif 的相互作用
- 批准号:
9204296 - 财政年份:2009
- 资助金额:
$ 51.03万 - 项目类别:
Understanding The Structural Basis of APOBEC Functions
了解 APOBEC 功能的结构基础
- 批准号:
7790588 - 财政年份:2009
- 资助金额:
$ 51.03万 - 项目类别:
Understanding The Structural Basis of APOBEC Functions
了解 APOBEC 功能的结构基础
- 批准号:
8244450 - 财政年份:2009
- 资助金额:
$ 51.03万 - 项目类别:
Structural Basis of APOBEC Functions and Interactions with HIV-Vif
APOBEC 功能的结构基础以及与 HIV-Vif 的相互作用
- 批准号:
9537133 - 财政年份:2009
- 资助金额:
$ 51.03万 - 项目类别:
Understanding The Structural Basis of APOBEC Functions
了解 APOBEC 功能的结构基础
- 批准号:
8053875 - 财政年份:2009
- 资助金额:
$ 51.03万 - 项目类别:
Structural Basis of APOBEC Functions and HIV Restriction
APOBEC 功能和 HIV 限制的结构基础
- 批准号:
10647803 - 财政年份:2009
- 资助金额:
$ 51.03万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 51.03万 - 项目类别:
Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 51.03万 - 项目类别:
Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 51.03万 - 项目类别:
Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 51.03万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 51.03万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 51.03万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 51.03万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 51.03万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 51.03万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 51.03万 - 项目类别:
Research Grant