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

基本信息

  • 批准号:
    9899099
  • 负责人:
  • 金额:
    $ 37.18万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-01-01 至 2022-03-31
  • 项目状态:
    已结题

项目摘要

Project Summary Proteins from the Fanconi anemia (FA) pathway play an integral role in DNA repair by homologous recombination (HR). FA is a multigenic disorder marked by progressive bone marrow failure and a strong cancer predisposition. Numerous studies have linked mutations in FA genes to familial breast, pancreatic, and other cancers, and have also provided ample evidence to implicate silencing of FA genes in the etiology of sporadic cancers. FA cells are hypersensitive to radiation and other DNA damaging agents, DNA crosslinking chemicals and reactive aldehydes in particular, prone to DNA replicative stress, and exhibit chromosome fragility. These phenotypic manifestations stem from defects in DNA damage signaling and repair, and FA protein functional and physical interactions have indicated an important link to the familial breast cancer proteins BRCA1 and BRCA2. The involvement of the FA/BRCA-dependent DNA damage response in cancer suppression underscores the need to understand the mechanistic underpinnings of this genome maintenance pathway. In this project, we will employ a combination of biochemical and in vivo approaches to test the novel hypotheses that the FA pathway coordinates the prevention and resolution of genotoxic structures resulting from aberrant transcription events and HR. Aim 1 will focus on the mechanism whereby the ID2 complex and UAF1-containing complexes engage nucleic acid containing structures and activate HR. Aim 2 will explore how the FANCM-BLM axis resolves pathogenic RNA containing and other nucleic acid intermediates in a way that regulates HR activities. The success of this project is assured by the complementary expertise of the two participating Yale groups, led by Dr Patrick Sung and Dr Gary Kupfer, and an exceptionally strong collaborative framework within the broader Yale community. In addition, the PIs have enlisted two investigators, Dr. Claudia Wiese and Dr. Andres Aguilera, whose expertise will even more elegantly allow the team to interrogate this novel area of genomic instability. These attributes help ensure that findings of the highest possible impact will be obtained. Since the biology of FA intersects with cancer biology in general, our project promises to shed light on critical processes of genomic surveillance as well as common themes of oncogenesis. We expect our studies to yield insight into common pathways of cancer and to identify novel targets for manipulation in cancer therapy.
项目摘要 来自范可尼贫血(FA)途径的蛋白质在DNA修复中起着不可或缺的作用, 重组(HR)。FA是一种多基因疾病,以进行性骨髓衰竭为标志, 很强的癌症易感性许多研究将FA基因突变与家族性乳腺癌联系起来, 胰腺癌和其他癌症,也提供了充分的证据表明FA沉默 基因在散发性癌症病因中的作用。FA细胞对辐射和其他DNA高度敏感 损伤剂,DNA交联化学品和反应性醛,特别是,易于DNA 复制压力,并表现出染色体脆性。这些表型表现源于 DNA损伤信号传导和修复的缺陷,以及FA蛋白的功能和物理相互作用, 表明与家族性乳腺癌蛋白BRCA 1和BRCA 2有重要联系。的 FA/BRCA依赖性DNA损伤反应参与癌症抑制强调 需要了解这一基因组维持途径的机制基础。 在这个项目中,我们将采用生物化学和体内方法相结合的方法来测试新的 假设FA途径协调遗传毒性结构的预防和解决 目的1将集中在机制,其中 ID 2复合物和含有UAF 1的复合物与含有核酸的结构接合并激活 HR.目的2将探讨FANCM-BLM轴如何解决致病性RNA含有和其他 核酸中间体的方式,调节HR活动。这个项目的成功是 由帕特里克宋博士领导的两个参与耶鲁小组的互补专业知识保证了这一点 和加里库普弗博士,以及在更广泛的耶鲁大学内部非常强大的合作框架 社区此外,PI还招募了两名调查员,克劳迪娅·威斯博士和安德烈斯博士 阿奎莱拉,其专业知识将更优雅地允许团队询问这个新的领域, 基因组不稳定性这些属性有助于确保具有最大可能影响的调查结果将被 得到了由于FA的生物学与癌症生物学一般交叉,我们的项目有望 阐明了基因组监测的关键过程以及肿瘤发生的共同主题。 我们希望我们的研究能够深入了解癌症的常见途径并确定新的靶点 用于癌症治疗

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 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:
    $ 37.18万
  • 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:
    $ 37.18万
  • 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:
    $ 37.18万
  • 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:
    $ 37.18万
  • 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:
    $ 37.18万
  • 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:
    $ 37.18万
  • 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:
    $ 37.18万
  • 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:
    $ 37.18万
  • 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:
    $ 37.18万
  • 项目类别:
The Fanconi Anemia Core and D2 Complexes
Fanconi 贫血核心和 D2 复合物
  • 批准号:
    7440298
  • 财政年份:
    2000
  • 资助金额:
    $ 37.18万
  • 项目类别:
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