Structural Biology of XPB and XPD Helicases
XPB 和 XPD 解旋酶的结构生物学
基本信息
- 批准号:7563283
- 负责人:
- 金额:$ 29.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-04-01 至 2011-02-28
- 项目状态:已结题
- 来源:
- 关键词:ATP phosphohydrolaseArchitectureBiochemicalBiochemistryBiologicalBiological ProcessBiophysicsCell DeathCockayne SyndromeComplexDNADNA DamageDNA RepairDefectDiseaseERCC3 geneElectronsEukaryotaEventFigs - dietaryGene MutationGenetic TranscriptionGerm-Line MutationHomologous GeneHumanIn VitroInheritedKnowledgeLaboratoriesLeadLengthLinkMalignant NeoplasmsMapsMediatingMental RetardationMicroscopicMolecularMolecular ConformationMolecular StructureMutationNerve DegenerationNucleotide Excision RepairOutcomePathway interactionsPatientsPhenotypePredispositionPremature aging syndromeProcessProteinsRepair ComplexResolutionRoleSkin CancerSpecificityStructureStructure-Activity RelationshipSyndromeTestingTranscription InitiationTranscription-Coupled RepairTrichothiodystrophyXPGC proteinXeroderma Pigmentosumbasecancer cellclinical phenotypedisease phenotypedisease-causing mutationhelicasehuman diseasein vivomutantprotein protein interactionrepairedresearch studystructural biologytranscription factor TFIIH
项目摘要
Hereditary mutations in the DNA helicases XPB and XPD lead to human diseases with different
phenotypes reflecting increased cancers or increased cell death: xeroderma pigmentosum (XP), XP-
linked Cockayne syndrome (CS), and trichothiodystrophy (TTD). These diseases reflect the disruption of
different cellular pathways: Defective nucleotide-excision repair (NER) results in XP, perturbed
transcription-coupled repair (TCR) leads to CS, and transcription abnormalities combined with defective
NER cause TTD. In humans, XPB and XPD helicases are part of the ten subunit TFIIH
transcription/repair complex, but disease-causing mutations cluster in XPB and particularly XPD rather
than in the other TFIIH proteins, excepting TFB5, so these XP helicases appear key to controlling
coordination of transcription and repair. Furthermore, the repair proteins XPG and CSB interact with the
XP helicases in TCR. However, there is little knowledge at the molecular level about XPB and XPD,
their helicase and repair activities, or their interactions with TFB5, CSB and XPG. We aim to
understand the molecular features underlying the specificity, activity, conformational controls and
pathway coordination by the XPB and XPD helicases. Our hypothesis is that well-defined architectures,
conformational states, and molecular interfaces of XPB and XPD helicases provide critical controls for
transcription, NER, and TCR. We furthermore propose that characterizations of these features and their
disruption by disease-causing mutations will provide a molecular basis to directly connect the inherited
gene mutations to disease phenotypes. To test this, we herein propose to integrate structural and
biophysical experiments (Tainer laboratory) with biochemical and biological experiments (Cooper
laboratory). Our experiments on XPB and XPD domains and full-length proteins, their archaeal
homologues, and their key assemblies will establish molecular architectures, conformational switching
mechanisms, and allosteric interactions. We expect to characterize a prototypical set of helicase
structures, their complexes with DNA and with protein partners, and to define the key interactions for
their activities. The anticipated outcome of the proposed cross-disciplinary experiments is a molecular
picture of the protein-DNA complexes, protein-protein interactions and functional states that orchestrate
transcription and repair events mediated by XPB and XPD as components of TFIIH. These results will
help provide a detailed molecular understanding of the processes that underlie the cancer and cell
death disease phenotypes associated with XPB, XPD, TFB5, CSB and XPG patient mutations.
DNA解旋酶XPB和XPD的遗传突变导致人类不同的疾病
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)
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John A. Tainer其他文献
Molecular model of TFIIH recruitment to the transcription-coupled repair machinery
TFIIH 招募到转录偶联修复机制的分子模型
- DOI:
10.1038/s41467-025-57593-0 - 发表时间:
2025-03-08 - 期刊:
- 影响因子:15.700
- 作者:
Tanmoy Paul;Chunli Yan;Jina Yu;Susan E. Tsutakawa;John A. Tainer;Dong Wang;Ivaylo Ivanov - 通讯作者:
Ivaylo Ivanov
DNA repair without flipping out
DNA 修复而不抓狂
- DOI:
10.1038/nature15646 - 发表时间:
2015-10-28 - 期刊:
- 影响因子:48.500
- 作者:
David S. Shin;John A. Tainer - 通讯作者:
John A. Tainer
A prismatic view of the epigenetic-metabolic regulatory axis in breast cancer therapy resistance
乳腺癌治疗耐药中表观遗传-代谢调节轴的棱柱形视图
- DOI:
10.1038/s41388-024-03054-9 - 发表时间:
2024-05-08 - 期刊:
- 影响因子:7.300
- 作者:
Chandrima Das;Apoorva Bhattacharya;Swagata Adhikari;Atanu Mondal;Payel Mondal;Santanu Adhikary;Siddhartha Roy;Kenneth Ramos;Kamlesh K. Yadav;John A. Tainer;Tej K. Pandita - 通讯作者:
Tej K. Pandita
Proteines de fusion ciblees par clycosaminoglycane, leurs conception, construction et compositions
糖胺聚糖融合蛋白、概念、结构和成分
- DOI:
- 发表时间:
1991 - 期刊:
- 影响因子:0
- 作者:
John A. Tainer;Leslie A. Kuhn;Maurice Boissinot;Cindy L. Fisher;Hans E. Parge;J. H. Griffin;Guy Mullenbach;Robert A. Hallewell - 通讯作者:
Robert A. Hallewell
Multiscale Modeling of PCNA - Ubiquitin Interactions
- DOI:
10.1016/j.bpj.2009.12.2087 - 发表时间:
2010-01-01 - 期刊:
- 影响因子:
- 作者:
Ivaylo Ivanov;Adam Van Wynsberghe;John A. Tainer;J. Andrew McCammon - 通讯作者:
J. Andrew McCammon
John A. Tainer的其他文献
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{{ truncateString('John A. Tainer', 18)}}的其他基金
Mesocale And Nanoscale Technologies Integrated by Structures for DNA Repair Complexes (MANTIS-DRC)
DNA 修复复合物结构集成的介观和纳米技术 (MANTIS-DRC)
- 批准号:
10687040 - 财政年份:2018
- 资助金额:
$ 29.84万 - 项目类别:
Mesocale And Nanoscale Technologies Integrated by Structures for DNA Repair Complexes (MANTIS-DRC)
DNA 修复复合物结构集成的介观和纳米技术 (MANTIS-DRC)
- 批准号:
10251045 - 财政年份:2018
- 资助金额:
$ 29.84万 - 项目类别:
MINOS (Macromolecular Insights on Nucleic acids Optimized by Scattering)
MINOS(通过散射优化核酸的大分子见解)
- 批准号:
8840824 - 财政年份:2012
- 资助金额:
$ 29.84万 - 项目类别:
MINOS (Macromolecular Insights on Nucleic acids Optimized by Scattering)
MINOS(通过散射优化核酸的大分子见解)
- 批准号:
8656719 - 财政年份:2012
- 资助金额:
$ 29.84万 - 项目类别:
MINOS (Macromolecular Insights on Nucleic acids Optimized by Scattering)
MINOS(通过散射优化核酸的大分子见解)
- 批准号:
8469234 - 财政年份:2012
- 资助金额:
$ 29.84万 - 项目类别:
MINOS (Macromolecular Insights on Nucleic acids Optimized by Scattering)
MINOS(通过散射优化核酸的大分子见解)
- 批准号:
8475491 - 财政年份:2012
- 资助金额:
$ 29.84万 - 项目类别:
Structural Biology of XPB and XPD Helicases
XPB 和 XPD 解旋酶的结构生物学
- 批准号:
8212285 - 财政年份:2006
- 资助金额:
$ 29.84万 - 项目类别:
Structural Biology of XPB and XPD Helicases
XPB 和 XPD 解旋酶的结构生物学
- 批准号:
7767763 - 财政年份:2006
- 资助金额:
$ 29.84万 - 项目类别:
Structural Biology of XPB and XPD Helicases
XPB 和 XPD 解旋酶的结构生物学
- 批准号:
7096103 - 财政年份:2006
- 资助金额:
$ 29.84万 - 项目类别:
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