The Fanconi Anemia Core and D2 Complexes

Fanconi 贫血核心和 D2 复合物

基本信息

  • 批准号:
    7440298
  • 负责人:
  • 金额:
    $ 36.71万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2000
  • 资助国家:
    美国
  • 起止时间:
    2000-09-10 至 2010-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The study of rare genetic disorders of cancer susceptibility, such as Fanconi anemia (FA) have led to seminal advances in cancer biology as a whole. The hallmark of FA is genomic instability and DNA damage hypersensitivity, but the normal function of the FA pathway or mechanism leading to cancer in the affected patients remains unknown. FA is accounted for by multiple complementation groups corresponding to at least 8 cloned genes whose encoded proteins contain few functional motifs. What is known is that the FA pathway interacts with other more defined pathways involved in cellular response to DNA damage, such as ATM and BRCA1. The Kupfer laboratory has established that FA proteins such as FANCA and FANCG phosphorylated, that the FA core complex (composed of at least 5 FA proteins) localizes to at least 3 subcellular compartments, including chromatin, and that the core complex binds to additional non-characterized proteins. This proposal centers on the analysis of posttranslational modifications of the FA proteins FANCA and FANCG and on detecting new binding proteins and determining their function. This would shed light on the long-term goal of the Kupfer laboratory: define the mechanisms of genomic instability caused by FA as well as understand the normal function of the FA proteins. In this proposal the experiments proposed address the central hypothesis: that the phosphorylation of FANCA and FANCG regulate proper localization to chromatin and that a novel FA binding protein, RBM10, has RNA binding activity critical for this localization. The work proposed will 1) determine the cause and effect of FANCA and FANCG phosphorylation, 2) analyze RBM10 and RNA function in the FA core complex, and 3) focus on purifying additional FA core complex and FANCD2 binding proteins, especially from chromatin. This research is significant because it sheds light on a mechanism of genomic instability at the level of the functional genetic unit of the cell: chromatin. Because the response to DNA damage involves numerous intersecting pathways, defining the function of FA proteins will allow us to link these disparate pathways in a mechanism explaining cancer formation.
描述(由申请人提供):对癌症易感性的罕见遗传性疾病(如范可尼贫血(FA))的研究导致了整个癌症生物学的重大进展。FA的标志是基因组不稳定性和DNA损伤超敏反应,但FA通路的正常功能或导致受影响患者癌症的机制仍然未知。FA是由多个互补基团,对应于至少8个克隆的基因,其编码的蛋白质含有很少的功能基序。已知的是,FA通路与其他更明确的通路相互作用,这些通路参与对DNA损伤的细胞反应,如ATM和BRCA 1。Kupfer实验室已经确定FA蛋白(如FANCA和FANCG)磷酸化,FA核心复合物(由至少5种FA蛋白组成)定位于至少3个亚细胞区室,包括染色质,并且核心复合物结合其他非特征蛋白。该建议集中在FA蛋白FANCA和FANCG的翻译后修饰的分析和检测新的结合蛋白,并确定其功能。这将有助于Kupfer实验室的长期目标:确定FA引起的基因组不稳定性的机制,以及了解FA蛋白的正常功能。在该提案中,提出的实验解决了中心假设:FANCA和FANCG的磷酸化调节染色质的正确定位,并且新型FA结合蛋白RBM 10具有对这种定位至关重要的RNA结合活性。这项工作将1)确定FANCA和FANCG磷酸化的原因和影响,2)分析RBM10和RNA在FA核心复合物中的功能,3)专注于纯化额外的FA核心复合物和FANCD 2结合蛋白,特别是从染色质中纯化。这项研究意义重大,因为它揭示了细胞功能遗传单位染色质水平上基因组不稳定性的机制。由于对DNA损伤的反应涉及许多交叉途径,因此确定FA蛋白的功能将使我们能够将这些不同的途径联系起来,解释癌症形成的机制。

项目成果

期刊论文数量(0)
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会议论文数量(0)
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Gary M. Kupfer其他文献

Complex Formation between FANCD2 and the Splicing Factor SRSF1 Helps Prevent R-Loop Accumulation through mRNA Export Regulation
  • DOI:
    10.1182/blood-2022-166798
  • 发表时间:
    2022-11-15
  • 期刊:
  • 影响因子:
  • 作者:
    Anne Olazabal Herrero;Fengshan Liang;Arijit Dutta;Yuxin Huang;Zhuobin Liang;Abhishek K Gupta;Li Lan;Manoj M Pillai;Patrick Sung;Gary M. Kupfer
  • 通讯作者:
    Gary M. Kupfer
The Fanconi anaemia proteins, FAA and FAC interact to form a nuclear complex
范可尼贫血蛋白(FAA)和 FAC 相互作用形成一个核复合物。
  • DOI:
    10.1038/ng1297-487
  • 发表时间:
    1997-12-01
  • 期刊:
  • 影响因子:
    29.000
  • 作者:
    Gary M. Kupfer;Dieter Näf;Ahmed Suliman;Michael Pulsipher;Alan D. D'Andrea
  • 通讯作者:
    Alan D. D'Andrea
A ROS-mediated oxidation-O-GlcNAcylation cascade governs ferroptosis
一个由 ROS 介导的氧化-O-GlcNAcylation 级联调控铁死亡
  • DOI:
    10.1038/s41556-025-01722-w
  • 发表时间:
    2025-07-18
  • 期刊:
  • 影响因子:
    19.100
  • 作者:
    Hemeng Zhang;Jialin Ma;Chunyan Hou;Xuehui Luo;Shiya Zhu;Yihan Peng;Changmin Peng;Ping Li;Heng Meng;Yuqi Xia;Zhinuo Jiang;Susree Modepalli;Anju Duttargi;Gary M. Kupfer;Mengjiao Cai;Heng Zhang;Junfeng Ma;Juanjuan Li;Suxia Han;Huadong Pei
  • 通讯作者:
    Huadong Pei

Gary M. Kupfer的其他文献

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{{ truncateString('Gary M. Kupfer', 18)}}的其他基金

Mechanistic Dissection of the Falconi Anemia Pathway of DNA Damage Response and Repair
法尔科尼贫血 DNA 损伤反应和修复途径的机制剖析
  • 批准号:
    9899099
  • 财政年份:
    2019
  • 资助金额:
    $ 36.71万
  • 项目类别:
Mechanistic Dissection of the BRCA1-SETX-dependent Pathway of R-loop Avoidance and Genome Maintenance
R 环避免和基因组维护的 BRCA1-SETX 依赖性途径的机制剖析
  • 批准号:
    10537108
  • 财政年份:
    2013
  • 资助金额:
    $ 36.71万
  • 项目类别:
Mechanistic Dissection of the Fanconi Anemia Pathway of DNA Damage Response and R
DNA 损伤反应和 R 范可尼贫血途径的机制剖析
  • 批准号:
    8505689
  • 财政年份:
    2013
  • 资助金额:
    $ 36.71万
  • 项目类别:
Mechanistic Dissection of the Fanconi Anemia Pathway of DNA Damage Response and R
DNA 损伤反应和 R 范可尼贫血途径的机制剖析
  • 批准号:
    8641673
  • 财政年份:
    2013
  • 资助金额:
    $ 36.71万
  • 项目类别:
Mechanistic Dissection of the BRCA1-SETX-dependent Pathway of R-loop Avoidance and Genome Maintenance
R 环避免和基因组维护的 BRCA1-SETX 依赖性途径的机制剖析
  • 批准号:
    10641022
  • 财政年份:
    2013
  • 资助金额:
    $ 36.71万
  • 项目类别:
Mechanistic Dissection of the Fanconi Anemia Pathway of DNA Damage Response and R
DNA 损伤反应和 R 范可尼贫血途径的机制剖析
  • 批准号:
    8826073
  • 财政年份:
    2013
  • 资助金额:
    $ 36.71万
  • 项目类别:
HTLV I Tax1 protein chemosensitization of p53 mutant tumors
HTLV I Tax1 蛋白对 p53 突变肿瘤的化疗增敏
  • 批准号:
    8053781
  • 财政年份:
    2010
  • 资助金额:
    $ 36.71万
  • 项目类别:
HTLV I Tax1 protein chemosensitization of p53 mutant tumors
HTLV I Tax1 蛋白对 p53 突变肿瘤的化疗增敏
  • 批准号:
    7872281
  • 财政年份:
    2010
  • 资助金额:
    $ 36.71万
  • 项目类别:
FANCD2 interaction with mismatch repair proteins and MCM2-7
FANCD2 与错配修复蛋白和 MCM2-7 的相互作用
  • 批准号:
    8616392
  • 财政年份:
    2000
  • 资助金额:
    $ 36.71万
  • 项目类别:
FANCD2 interaction with mismatch repair proteins and MCM2-7
FANCD2 与错配修复蛋白和 MCM2-7 的相互作用
  • 批准号:
    8231274
  • 财政年份:
    2000
  • 资助金额:
    $ 36.71万
  • 项目类别:

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