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
基本信息
- 批准号:10641022
- 负责人:
- 金额:$ 48.52万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-04-01 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:AdultAdvanced Malignant NeoplasmBARD1 geneBRCA1 geneBiochemicalBiologicalBiological AssayBiological ProcessBiologyBone marrow failureCell ExtractsCell SurvivalCell physiologyCellsCellular biologyChromosomal translocationCo-ImmunoprecipitationsCollaborationsComplexCoupledDNADNA DamageDNA Double Strand BreakDNA RepairDNA Repair PathwayDNA StructureDNA biosynthesisDNA lesionDNA replication forkDataDiagnosisDiseaseDissectionEventFamilyFanconi&aposs AnemiaGenetic ModelsGenetic RecombinationGenetic TranscriptionGenomeGenome StabilityGrantHeadHematopoiesisHybridsIn VitroJoint VenturesLinkMaintenanceMalignant Childhood NeoplasmMalignant NeoplasmsMapsMediatingMessenger RNAMethodsModelingMutagenesisMutationNatureNeoplastic Cell TransformationNucleic Acid Amplification TestsNucleic Acid BindingNucleic AcidsObstructionPaperPathologicPathway interactionsPediatric OncologistPhysiciansPhysiologicalProcessProductivityPropertyProteinsPublishingRNARNA SplicingRepair EnzymologyResearch PersonnelResolutionRoleSF1ScientistSingle-Stranded DNASiteStressStructureStructure-Activity RelationshipSubstrate SpecificitySystemTestingTimeTranscriptTumor SuppressionTumor Suppressor Proteinscancer preventioncausal variantgenome integrityhelicaseinsightmultidisciplinarymutantnervous system disordernovelnucleic acid structurepreservationreconstitutionreplication stressresponsesynergismtumorigenesis
项目摘要
Project Summary
Maintenance of genomic integrity depends on the ability of cells to repair damaged DNA and resolve
transcription-replication conflicts. In this regard, R-loops, three-stranded nucleic acid structures that
harbor an RNA transcript hybridized to a DNA template, can compromise genome stability in multiple
ways. Specifically, the ssDNA within the R-loop structure is vulnerable to nucleolytic cleavage, resulting
in transcription-associated mutagenesis or transcription-associated recombination. Moreover, collisions
of the DNA replication machinery with R-loops can cause replication fork collapse, DNA double-strand
breaks (DSBs), fork fusions, and chromosome translocations, which can then lead to neoplastic
transformation and tumorigenesis.
This competitive continuation of our MPI grant leverages our unique expertise in DNA repair enzymology
and cell biology modeling to delineate the structure-function of an R-loop resolution machinery comprised
of the SF1 family helicase Senataxin (SETX) and the tumor suppressor complex BRCA1-BARD1. In
Specific Aim 1, we will define the unusually versatile nucleic acid unwinding activity of SETX and test
the hypothesis that SETX resolves R loops directly through specific unwinding activity. Specific Aim 2
will determine the role of BRCA1-BARD1 in SETX-mediated R-loop resolution to test the hypothesis that
BRCA1-BARD1 cooperates with SETX to resolve pathological R-loops by interrogating SETX and
BRCA1-BARD1 in our reconstituted biochemical systems and in cells.
This MPI renewal is based on the longstanding and productive collaboration between Dr Patrick Sung, a
leading DNA repair enzymologist, and Dr Gary Kupfer, a physician-scientist who has utilized the genetic
model of Fanconi anemia to advance understanding of DNA repair pathways and mechanisms.
Together, with numerous coauthored papers of high significance, our continuing collaborative endeavors
promise to exert impact of the highest degree and to provide insight into the mechanistic underpinnings
of a major genome maintenance pathway that is linked to tumor suppression pathways.
项目总结
项目成果
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A novel role for non-ubiquitinated FANCD2 in response to hydroxyurea-induced DNA damage.
- DOI:10.1038/onc.2015.68
- 发表时间:2016-01-07
- 期刊:
- 影响因子:8
- 作者:Chen X;Bosques L;Sung P;Kupfer GM
- 通讯作者:Kupfer GM
Role of RAD51AP1 in homologous recombination DNA repair and carcinogenesis.
- DOI:10.1016/j.dnarep.2017.09.008
- 发表时间:2017-11
- 期刊:
- 影响因子:3.8
- 作者:Pires E;Sung P;Wiese C
- 通讯作者:Wiese C
Structural insights into 5' flap DNA unwinding and incision by the human FAN1 dimer.
对人类 FAN1 二聚体 5 瓣 DNA 解旋和切割的结构见解。
- DOI:10.1038/ncomms6726
- 发表时间:2014
- 期刊:
- 影响因子:16.6
- 作者:Zhao,Qi;Xue,Xiaoyu;Longerich,Simonne;Sung,Patrick;Xiong,Yong
- 通讯作者:Xiong,Yong
Homologous Recombination Repair in Biliary Tract Cancers: A Prime Target for PARP Inhibition?
- DOI:10.3390/cancers14102561
- 发表时间:2022-05-23
- 期刊:
- 影响因子:5.2
- 作者:Yin, Chao;Kulasekaran, Monika;Roy, Tina;Decker, Brennan;Alexander, Sonja;Margolis, Mathew;Jha, Reena C.;Kupfer, Gary M.;He, Aiwu R.
- 通讯作者:He, Aiwu R.
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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:
$ 48.52万 - 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:
$ 48.52万 - 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:
$ 48.52万 - 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:
$ 48.52万 - 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:
$ 48.52万 - 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:
$ 48.52万 - 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:
$ 48.52万 - 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:
$ 48.52万 - 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:
$ 48.52万 - 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:
$ 48.52万 - 项目类别:














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