Understanding the function of histone H3 as an oxidoreductase enzyme
了解组蛋白 H3 作为氧化还原酶的功能
基本信息
- 批准号:10545737
- 负责人:
- 金额:$ 43.73万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-01-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:Active SitesArchaeaBindingBinding SitesBiochemicalBiologicalBiologyCRISPR interferenceCRISPR screenCRISPR/Cas technologyCatalysisCatalytic DomainCell NucleusCell SeparationCell physiologyCellsChemistryChromatinChromatin StructureComplexCopperCoupledCytoplasmDNADataDestinationsDialysis procedureDimensionsDiseaseElectronsEnvironmentEnzymesEukaryotaEukaryotic CellEvolutionFoundationsGene ExpressionGenerationsGenesGeneticGenetic ScreeningGenomeHistone H3HistonesHomeostasisHumanHuman PathologyIn VitroIonsLinkLiteratureMalignant NeoplasmsMetabolismMitochondriaMitochondrial ProteinsModificationMolecularMolecular ChaperonesN-terminalNADPNerve DegenerationNucleosomesOxidoreductasePathway interactionsPhysiologicalPost-Translational Protein ProcessingProcessProteinsReactionRecombinantsReducing AgentsRegulationRespirationRoleSaccharomyces cerevisiaeSideSodium ChlorideStructureSystemTailTechnologyTestingVariantXenopusYeastschemical reactioncofactorcuprous iondeep sequencingdesigndimerenzyme activityepigenetic regulationepigenomegain of function mutationhistone modificationhuman diseaseloss of functionnoveloxidationprotein H(3)protein complexscreeningsuperoxide dismutase 1yeast genetics
项目摘要
PROJECT SUMMARY
This application proposes to investigate the newly discovered function of histone H3 as an oxidoreductase
enzyme, catalyzing the reduction of cupric (Cu+2) ions to the biousable cuprous (Cu+1) form. The eukaryotic
histone H3-H4 tetramer contains a putative Cu2+ binding site at the interface of the apposing H3 proteins with
unknown function. The coincident emergence of eukaryotes with global oxygenation, which challenged cellular
copper utilization, raised the possibility that histones may function in cellular copper homeostasis. We have
extensive evidence that histones are required for efficient use of copper inside cells, which depend on availability
of copper ions in their reduced, +1 oxidation state. It is the Cu+1 ions that are trafficked intracellularly by protein
chaperones to destination target proteins. We show that the H3-H4 tetramer, assembled from recombinant
histones, binds Cu2+ and catalyzes its reduction to Cu1+ in vitro. Loss- and gain-of-function mutations of the
putative active site residues correspondingly altered copper binding and the enzymatic activity, as well as
intracellular Cu1+ levels and copper-dependent activities such as mitochondrial respiration and superoxide
dismutase 1 (Sod1) function in S. cerevisiae. Our data have uncovered a function of the histone H3-H4 tetramer
with little precedence in literature, revealing that the eukaryotic genome is wrapped around an enzyme. We now
propose to develop a mechanistic understanding of this new function of histones and how it is regulated and
linked to cellular copper homeostasis. In Aim 1, we seek to understand the mechanism of catalysis by
determining the structure of copper-bound H3-H4 tetramer and the contributions of the residues in and around
the active site. In Aim 2, we will discern how the enzyme activity is regulated, especially through post-translational
modifications of histones and certain histone variants. The enzymatic activity of histones indicates that there
must be a previously undiscovered biological network that shuttles Cu2+ to histones and then distributes the
reaction product (Cu1+) to different parts of the cell for use by proteins in the nucleus, cytoplasm and
mitochondria. In Aim 3, we plan to systematically identify the protein effectors involved in this novel copper
biological network in yeast by utilizing a high-throughput CRISPR-interference (CRISPRi) technology. We aim
to identify the genes and pathways that integrate the enzymatic activity of histones with other cellular functions.
Our proposal will begin to build the scientific foundation for understanding chromatin structure and function as
an enzyme and its impact on eukaryotic biology with instructive consequences for the evolution of the eukaryotic
cell as well as a range of human pathologies such as cancer and neurodegeneration in which copper
homeostasis is altered.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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Siavash Kurdistani其他文献
Siavash Kurdistani的其他文献
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{{ truncateString('Siavash Kurdistani', 18)}}的其他基金
Understanding the function of histone H3 as an oxidoreductase enzyme
了解组蛋白 H3 作为氧化还原酶的功能
- 批准号:
10320937 - 财政年份:2021
- 资助金额:
$ 43.73万 - 项目类别:
Dynamics of Histone Acetylation in Cancer Cell Physiology
癌细胞生理学中组蛋白乙酰化的动态
- 批准号:
9302692 - 财政年份:2013
- 资助金额:
$ 43.73万 - 项目类别:
Dynamics of Histone Acetylation in Cancer Cell Physiology
癌细胞生理学中组蛋白乙酰化的动态
- 批准号:
8739627 - 财政年份:2013
- 资助金额:
$ 43.73万 - 项目类别:
Dynamics of Histone Acetylation in Cancer Cell Physiology
癌细胞生理学中组蛋白乙酰化的动态
- 批准号:
8563238 - 财政年份:2013
- 资助金额:
$ 43.73万 - 项目类别:
Dynamics of Histone Acetylation in Cancer Cell Physiology
癌细胞生理学中组蛋白乙酰化的动态
- 批准号:
8885769 - 财政年份:2013
- 资助金额:
$ 43.73万 - 项目类别:
A Blueprint for Oncogenic Epigenetic Reprogramming
致癌表观遗传重编程的蓝图
- 批准号:
7853988 - 财政年份:2009
- 资助金额:
$ 43.73万 - 项目类别:
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