The XPA scaffold protein in Nucleotide Excision Repair

核苷酸切除修复中的 XPA 支架蛋白

基本信息

  • 批准号:
    10334466
  • 负责人:
  • 金额:
    $ 31.24万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-02-09 至 2023-08-31
  • 项目状态:
    已结题

项目摘要

Nucleotide excision repair (NER) protects human cells by removing harmful DNA adducts formed by environmental toxins and solar UV irradiation. Defects in NER in humans lead to the DNA repair disorder xeroderma pigmentosum, which is characterized by high predisposition to skin cancer, neurological abnormalities and premature death. The repair of damaged DNA by NER also has a downside – it contributes significantly to the development of resistance of tumors to treatment with antitumor agents, in particular cis- and carboplatin, two of the most widely prescribed drugs in oncology. We propose to leverage the combined expertise of the Scharer and Chazin laboratories in chemistry, biochemistry, cell biology, structural biology, and small molecule discovery to elucidate how the scaffold protein XPA coordinates the assembly and organization of NER incision complexes. Despite its modest size (273 residues), XPA functions as the central scaffold of NER complexes, interacting with 4 key NER proteins as well as DNA. However, how XPA is recruited to the site of damage and positions other factors through its various interactions remains poorly understood. Moreover, given its essential role in organizing and orchestrating the trajectory of NER complexes, XPA is an attractive potential Achilles Heel to target for suppressing NER. Aim 1 will test the hypothesis that TFIIH recruits XPA to sites of UV damage through a proposed interaction interface involving the C-terminal region of XPA and the p8 subunit of TFIIH. We will biochemically and structurally characterize this interaction and determine how mutations in the interface that disturb this interaction affect NER in vitro and in vivo. Abolishing the interaction between XPA and TFIIH will also address the long-standing question of whether the steps following damage recognition are the same for global genome and transcription-coupled NER – the arrival of TFIIH and XPA is the first step common to both pathways. The action of TFIIH on damaged DNA creates an open “NER bubble” that provides a landing platform for XPA and RPA and is required for NER incision. The scaffolding function of XPA is reliant on its coordination with RPA, which binds the undamaged strand. Aim 2 will determine the molecular basis and functional implications of the coordinated action of XPA and RPA. Structural, biochemical, and biophysical approaches combined with cellular assays will test the hypothesis that the two interaction sites between XPA and RPA are simultaneously engaged and contribute to NER in a cooperative fashion. Based on these results, our expertise in fragment based molecular discovery will be used to develop and validate initial inhibitors targeting XPA-RPA interfaces. These studies are expected to provide: (i) dramatic new mechanistic insights into the central role of XPA in assembling and coordinating the NER machinery; (ii) the identity of XPA interaction surfaces that are critical to NER; (iii) proof of principle that interfaces between XPA and other NER factors are suitable targets for evaluating the potential of overcoming tumor resistance to DNA damaging therapies by suppressing NER.
核苷酸切除修复(NER)通过去除DNA中有害的加合物来保护人体细胞

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 }}

WALTER J. CHAZIN其他文献

WALTER J. CHAZIN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('WALTER J. CHAZIN', 18)}}的其他基金

The XPA scaffold protein in Nucleotide Excision Repair
核苷酸切除修复中的 XPA 支架蛋白
  • 批准号:
    10733350
  • 财政年份:
    2018
  • 资助金额:
    $ 31.24万
  • 项目类别:
Structural Biology of Multi-Domain Proteins and Multi-Protein Machinery in DNA Replication and Repair
DNA 复制和修复中多域蛋白和多蛋白机制的结构生物学
  • 批准号:
    10393403
  • 财政年份:
    2016
  • 资助金额:
    $ 31.24万
  • 项目类别:
Integrative Structural Biology in DNA Replication and Damage Response
DNA 复制和损伤反应中的综合结构生物学
  • 批准号:
    10796477
  • 财政年份:
    2016
  • 资助金额:
    $ 31.24万
  • 项目类别:
Structural Biology of Multi-Domain Proteins and Multi-Protein Machinery in DNA Replication and Repair
DNA 复制和修复中多域蛋白和多蛋白机制的结构生物学
  • 批准号:
    10382072
  • 财政年份:
    2016
  • 资助金额:
    $ 31.24万
  • 项目类别:
Integrative Structural Biology in DNA Replication and Damage Response
DNA 复制和损伤反应中的综合结构生物学
  • 批准号:
    10544307
  • 财政年份:
    2016
  • 资助金额:
    $ 31.24万
  • 项目类别:
Integrative Structural Biology in DNA Replication and Damage Response
DNA 复制和损伤反应中的综合结构生物学
  • 批准号:
    10330665
  • 财政年份:
    2016
  • 资助金额:
    $ 31.24万
  • 项目类别:
Integrative Structural Biology in DNA Replication and Damage Response
DNA 复制和损伤反应中的综合结构生物学
  • 批准号:
    10809376
  • 财政年份:
    2016
  • 资助金额:
    $ 31.24万
  • 项目类别:
Host-mediated zinc sequestration during Acinetobacter baumannii infection
鲍曼不动杆菌感染期间宿主介导的锌螯合
  • 批准号:
    10680779
  • 财政年份:
    2013
  • 资助金额:
    $ 31.24万
  • 项目类别:
Host-mediated zinc sequestration during Acinetobacter baumannii infection
鲍曼不动杆菌感染期间宿主介导的锌螯合
  • 批准号:
    10331783
  • 财政年份:
    2013
  • 资助金额:
    $ 31.24万
  • 项目类别:
Host-mediated zinc sequestration during Acinetobacter baumannii infection
鲍曼不动杆菌感染期间宿主介导的锌螯合
  • 批准号:
    8504420
  • 财政年份:
    2013
  • 资助金额:
    $ 31.24万
  • 项目类别:

相似海外基金

How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 31.24万
  • 项目类别:
    Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 31.24万
  • 项目类别:
    Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 31.24万
  • 项目类别:
    Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 31.24万
  • 项目类别:
    Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 31.24万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 31.24万
  • 项目类别:
    Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 31.24万
  • 项目类别:
    Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 31.24万
  • 项目类别:
    Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
  • 批准号:
    23K00129
  • 财政年份:
    2023
  • 资助金额:
    $ 31.24万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
  • 批准号:
    2883985
  • 财政年份:
    2023
  • 资助金额:
    $ 31.24万
  • 项目类别:
    Studentship
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了