Molecular Mechanisms of Transcription Initiation and DNA Repair

转录起始和DNA修复的分子机制

基本信息

  • 批准号:
    10581660
  • 负责人:
  • 金额:
    $ 46.85万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-03-01 至 2027-02-28
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ABSTRACT This application describes our research into essential molecular pathways of the human pathogen, Mycobacterium tuberculosis (Mtb), including studies of transcription regulation and DNA repair. Infection with Mtb results in over 10 million new cases of tuberculosis and 1.5 million deaths annually, making it the deadliest infection in the world. In addition, this health crisis continues to be exacerbated by the emergence of drug- resistant strains, which demands the discovery of new antibiotic agents. In addition, we are deepening and broadening our biophysical work elucidating mechanisms of eukaryotic transcription initiation via both ensemble and single-molecule experiments coupled with kinetic modeling of the process in both yeast and humans. Transcription is responsible for changes in gene expression patterns during development or in adaptation to environmental conditions. The recruitment of RNA polymerase (RNAP) to particular genes at particular times is performed by sets of general and gene-specific transcription factors during transcription initiation. We are studying the essential, operator-independent, global transcription factors of Mycobacterium tuberculosis, CarD and RbpA. These factors act by modulating the rates of isomerization into and out of the open complex intermediate in initiation and, contrary to intuition, appear able to act as either activators or repressors without recognizing DNA sequence directly. We will answer critical questions in the field regarding the sequence- and sigma-factor (i.e., stress-response) dependence of these factors as well as their roles in post-initiation phases of transcription. We are also studying links between the transcription and DNA repair in Mtb. Mycobacteria lack classically conserved mismatch repair pathways (MMR) and possess repair factors not seen in E. coli. In addition, we have recently uncovered a novel oxidative switch that activates the Mtb nucleotide excision repair enzyme (NER), UvrD1. We are currently investigating the biophysical nature of this switch, alternative activation pathways, and the ability of UvrD1 to interact with RNAP during transcription-coupled NER. Of particular interest, and providing a link between our studies, is the shared RNAP-binding site used by both CarD and UvrD1. Lastly, we are continuing our investigations of the kinetic intermediates underlying pre-initiation-complex (PIC) dependent transcription initiation. Specifically, we are determining the mechanism of DNA bubble expansion during initial transcription in both yeast and humans. Our single-molecule magnetic-tweezers experiments will provide high-resolution views of the mechanism of PIC function. We are also following up on our recent discoveries of differences between the activities of yeast and human TFIIH (the general transcription factor required for promoter unwinding) that may underly the distinct usage of transcription-start sites in these organisms. As PIC function underlies gene expression, our unique approaches will provide important advances in the study of human biology.
项目摘要/摘要 这项申请描述了我们对人类病原体基本分子途径的研究, 结核分枝杆菌(MTB),包括转录调控和DNA修复的研究。感染了 结核病每年导致1000多万新结核病病例和150万人死亡,使其成为死亡人数最多的 世界上最大的传染病。此外,毒品的出现继续加剧了这场健康危机。 耐药菌株,这需要发现新的抗生素制剂。此外,我们正在深化和 拓宽我们的生物物理工作,阐明真核转录启动的机制 以及单分子实验,结合酵母和人类的这一过程的动力学模型。 转录负责在发育或适应过程中基因表达模式的变化 环境条件。RNA聚合酶(RNAP)在特定时间对特定基因的募集是 在转录启动过程中由一组通用的和基因特异的转录因子执行。我们是 研究结核分枝杆菌基本的、非操作者依赖的全局转录因子 和RbpA。这些因素通过调节进入和离开开放复合体的异构化速率起作用 在启动中居中,与直觉相反,似乎能够在没有直觉的情况下充当激活者或抑制者 直接识别DNA序列。我们将回答该领域有关序列的关键问题--以及 这些因子的Sigma因子(即应激反应)依赖性及其在启动后阶段中的作用 抄写。 我们还在研究结核分枝杆菌的转录和DNA修复之间的联系。分枝杆菌缺乏经典 保守的错配修复途径(MMR),并具有在大肠杆菌中未见的修复因子。此外,我们还有 最近发现了一种新的氧化开关,可以激活线粒体核苷酸切除修复酶(NER), Uvrd1。我们目前正在研究这种开关的生物物理性质,替代激活途径,以及 在转录偶联NER过程中,UvrD1与RNAP相互作用的能力。特别感兴趣,并提供 我们研究之间的一个联系,是CARD和UvrD1使用的共享RNAP结合位点。 最后,我们正在继续研究引发前复合体背后的动力学中间体。 (图)依赖转录起始。具体地说,我们正在确定DNA泡沫化的机制 酵母和人类在初始转录过程中的扩增。我们的单分子磁镊子 实验将提供对PIC作用机制的高分辨率观察。我们也在跟进 我们最近发现的酵母和人类TFIIH(一般转录)活性的差异 启动子解离所需的因子),这可能低于转录起始点在这些 有机体。由于PIC功能是基因表达的基础,我们独特的方法将提供重要的进展 在人类生物学的研究中。

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 }}

Eric A Galburt其他文献

Eric A Galburt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('Eric A Galburt', 18)}}的其他基金

Molecular Mechanisms of Transcription Initiation and DNA Repair
转录起始和DNA修复的分子机制
  • 批准号:
    10797632
  • 财政年份:
    2022
  • 资助金额:
    $ 46.85万
  • 项目类别:
Molecular Mechanisms of Transcription Initiation and DNA Repair
转录起始和DNA修复的分子机制
  • 批准号:
    10330862
  • 财政年份:
    2022
  • 资助金额:
    $ 46.85万
  • 项目类别:
Kinetic regulation of mycobacterial transcription
分枝杆菌转录的动力学调控
  • 批准号:
    9810951
  • 财政年份:
    2019
  • 资助金额:
    $ 46.85万
  • 项目类别:
Kinetic regulation of mycobacterial transcription
分枝杆菌转录的动力学调控
  • 批准号:
    9982385
  • 财政年份:
    2019
  • 资助金额:
    $ 46.85万
  • 项目类别:
Kinetic regulation of mycobacterial transcription
分枝杆菌转录的动力学调控
  • 批准号:
    10026742
  • 财政年份:
    2019
  • 资助金额:
    $ 46.85万
  • 项目类别:
MECHANISMS OF EUKARYOTIC TRANSCRIPTION INITIATION
真核转录起始机制
  • 批准号:
    9335931
  • 财政年份:
    2016
  • 资助金额:
    $ 46.85万
  • 项目类别:
INVESTIGATING NOVEL MECHANISMS OF TRANSCRIPTION INITIATION REGULATION IN MYCOBACTERIA
研究分枝杆菌转录起始调控的新机制
  • 批准号:
    9266954
  • 财政年份:
    2013
  • 资助金额:
    $ 46.85万
  • 项目类别:
INVESTIGATING NOVEL MECHANISMS OF TRANSCRIPTION INITIATION REGULATION IN MYCOBACT
研究 Mycobact 转录起始调控的新机制
  • 批准号:
    8563329
  • 财政年份:
    2013
  • 资助金额:
    $ 46.85万
  • 项目类别:
INVESTIGATING NOVEL MECHANISMS OF TRANSCRIPTION INITIATION REGULATION IN MYCOBACT
研究 Mycobact 中转录起始调控的新机制
  • 批准号:
    8695415
  • 财政年份:
    2013
  • 资助金额:
    $ 46.85万
  • 项目类别:
INVESTIGATING NOVEL MECHANISMS OF TRANSCRIPTION INITIATION REGULATION IN MYCOBACT
研究 Mycobact 中转录起始调控的新机制
  • 批准号:
    8881231
  • 财政年份:
    2013
  • 资助金额:
    $ 46.85万
  • 项目类别:

相似海外基金

Bridging the Gap: Next-Gen Tools for Accurate Prediction of Disordered Protein Binding Sites
弥合差距:准确预测无序蛋白质结合位点的下一代工具
  • 批准号:
    24K15172
  • 财政年份:
    2024
  • 资助金额:
    $ 46.85万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Design of protein crystal templates with multiple binding sites for tracking metal complex reactions.
设计具有多个结合位点的蛋白质晶体模板,用于跟踪金属络合物反应。
  • 批准号:
    23K04928
  • 财政年份:
    2023
  • 资助金额:
    $ 46.85万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Dynamic changes in PIP2 binding sites and their impact on axonal targeting and function of epilepsy-associated KCNQ/Kv7 channels
PIP2 结合位点的动态变化及其对癫痫相关 KCNQ/Kv7 通道的轴突靶向和功能的影响
  • 批准号:
    10744934
  • 财政年份:
    2023
  • 资助金额:
    $ 46.85万
  • 项目类别:
Computational methods to identify small molecule RNA binding sites
识别小分子 RNA 结合位点的计算方法
  • 批准号:
    573688-2022
  • 财政年份:
    2022
  • 资助金额:
    $ 46.85万
  • 项目类别:
    University Undergraduate Student Research Awards
Identification of potential drug binding sites within allosteric networks in cyclic nucleotide modulated channels
环核苷酸调节通道变构网络内潜在药物结合位点的鉴定
  • 批准号:
    10704557
  • 财政年份:
    2022
  • 资助金额:
    $ 46.85万
  • 项目类别:
Identification of potential drug binding sites within allosteric networks in cyclic nucleotide modulated channels
环核苷酸调节通道变构网络内潜在药物结合位点的鉴定
  • 批准号:
    10537846
  • 财政年份:
    2022
  • 资助金额:
    $ 46.85万
  • 项目类别:
Identifying new types of inhibitors in quinone binding sites in photosynthetic enzymes
鉴定光合酶醌结合位点的新型抑制剂
  • 批准号:
    2753921
  • 财政年份:
    2022
  • 资助金额:
    $ 46.85万
  • 项目类别:
    Studentship
Development of broad nanovaccines targeting diverse coronavirus receptor-binding sites
开发针对不同冠状病毒受体结合位点的广泛纳米疫苗
  • 批准号:
    10328140
  • 财政年份:
    2022
  • 资助金额:
    $ 46.85万
  • 项目类别:
Exploiting Water Network Perturbations in Protein Binding Sites
利用蛋白质结合位点的水网络扰动
  • 批准号:
    10621368
  • 财政年份:
    2021
  • 资助金额:
    $ 46.85万
  • 项目类别:
SBIR Phase I: Nonlinear optical method for identifying protein-ligand binding sites
SBIR 第一阶段:识别蛋白质-配体结合位点的非线性光学方法
  • 批准号:
    2111821
  • 财政年份:
    2021
  • 资助金额:
    $ 46.85万
  • 项目类别:
    Standard Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了