A Chemical Footprinting Approach towards Poly-ADP-Ribosylation-regulated Biomolecular Condensation
聚 ADP 核糖基化调节生物分子缩合的化学足迹方法
基本信息
- 批准号:10610165
- 负责人:
- 金额:$ 32.23万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2026-11-30
- 项目状态:未结题
- 来源:
- 关键词:ADP ribosylationAcylationAddressAmino AcidsAmyotrophic Lateral SclerosisAnimal ModelBindingBinding ProteinsBiologicalBiological ProcessBrainCell DeathCell NucleusCellsCellular StressCerebellar AtaxiaCessation of lifeChemicalsDNADNA DamageDNA RepairDataDiffuseEnzymesFDA approvedFamilyGeneticGenotoxic StressHeterogeneous-Nuclear RibonucleoproteinsHumanImidazoleIn VitroLengthMalignant NeoplasmsMalignant neoplasm of ovaryMass Spectrum AnalysisMediatingMembraneMessenger RNAMethodsModificationMolecular ConformationMutateNatureNeuronsNeurotoxinsNitrogenNuclearNuclear PoreNuclear ProteinNucleic AcidsOrganellesOxygenParkinson DiseasePathogenesisPathologicPathway interactionsPharmacologyPhase TransitionPhysical condensationPoly Adenosine Diphosphate RibosePoly(ADP-ribose) PolymerasesPolymersPost-Translational Protein ProcessingProcessProtein AnalysisProteinsProteomePublishingRNAReagentRecombinantsRegulationRoleSamplingSeedsSeriesSideSignal TransductionSiteStimulantStructureSurfaceSystemTraumatic Brain InjuryWorkacyl groupaspartylglutamatebasebiological adaptation to stressbiophysical toolsbrain dysfunctiondensityexperienceexperimental studygenotoxicityinhibitormalignant breast neoplasmmouse modelnervous system disorderneuron lossneurotoxicnovelprogramsprotein aggregationresponseself assemblysmall moleculespatiotemporal
项目摘要
Project Summary
Poly-ADP-ribosylation (PARylation) is a protein posttranslational modification (PTM) that is catalyzed by a
family of enzymes called Poly-ADP-ribose polymerases (PARPs). Among the various PARP enzymes, PARP1
is a nuclear protein that is critically involved in cell stress responses. The PARylation level in a quiescent cell is
usually very low. In response to genotoxic stress, PARP1 binds to nicked DNA and is rapidly activated,
resulting in the synthesis of a large number of PARylated proteins and initiation of the DNA damage repair
(DDR) mechanisms. Indeed, four PARP1 inhibitors have recently been approved by the FDA to treat BRCA-
mutated ovarian and/or breast cancers. Besides the role in regulating DDR in the context of human
malignancies, recent evidence suggests that PARylation serves as a death signal in neurons. Importantly,
genetic deletion or pharmacological inhibition of PARP1 offers profound protection against brain dysfunction in
the animal models of many neurological disorders (e.g., Parkinson’s disease, amyotrophic lateral sclerosis,
traumatic brain injury and cerebellar ataxia). PARP1 is directly activated by a variety of neurotoxic stimulants,
and aberrant PARylation promotes the formation of biomolecular condensates. Despite the established role of
PARylation in the regulation of phase-transition, the structural aspects of this process are elusive. To address
this, we will leverage our published work and the extensive experience of my lab. These preliminary data are
largely focused on two different programs. First, PARylation is a notorious PTM for mass spectrometrists,
because of its labile and heterogenous nature. We recently were able to overcome these challenges, and
develope a large-scale mass spectrometric approach towards comprehensive characterization of the Asp- and
Glu-PARylated proteome. Using this approach, we have defined the global PARylated proteome under various
genotoxic conditions. Second, biomolecular condensates are a class of membrane-less organelles, whose
structural dynamics are less amenable to traditional biophysical tools. To address this, we previously
developed a mass spectrometry-based chemical “footprinting” method for the structural analysis of these
protein fibrils. Based on these results, we will develop a novel, tunable footprinting approach for the
characterization of the structural dynamics of biomolecular condensates (Aim 1). Then we will use tunable
footprinting to study how PARylation regulates phase-transition in vitro (Aim 2) and in intact nuclei (Aim 3). The
information garnered from these studies will provide a fundamental understanding of this critical biological
process, paving the way for targeting PARP1 for the treatment of neurological disorders.
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)
会议论文数量(0)
专利数量(0)
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Yonghao Yu其他文献
Yonghao Yu的其他文献
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{{ truncateString('Yonghao Yu', 18)}}的其他基金
A Chemical Footprinting Approach towards Poly-ADP-Ribosylation-regulated Biomolecular Condensation
聚 ADP 核糖基化调节生物分子缩合的化学足迹方法
- 批准号:
10524783 - 财政年份:2022
- 资助金额:
$ 32.23万 - 项目类别:
A Chemical Footprinting Approach towards Poly-ADP-Ribosylation-regulated Biomolecular Condensation
聚 ADP 核糖基化调节生物分子缩合的化学足迹方法
- 批准号:
10389853 - 财政年份:2021
- 资助金额:
$ 32.23万 - 项目类别:
Site-Specific Antibody for Protein Poly-ADP-Ribosylation
蛋白质聚 ADP 核糖基化位点特异性抗体
- 批准号:
10610163 - 财政年份:2021
- 资助金额:
$ 32.23万 - 项目类别:
Site-Specific Antibody for Protein Poly-ADP-Ribosylation
蛋白质聚 ADP 核糖基化位点特异性抗体
- 批准号:
10231962 - 财政年份:2021
- 资助金额:
$ 32.23万 - 项目类别:
Posttranslational Regulation of Cell Growth and Stress Responses
细胞生长和应激反应的翻译后调节
- 批准号:
10676253 - 财政年份:2020
- 资助金额:
$ 32.23万 - 项目类别:
Posttranslational Regulation of Cell Growth and Stress Responses
细胞生长和应激反应的翻译后调节
- 批准号:
10610164 - 财政年份:2020
- 资助金额:
$ 32.23万 - 项目类别:
Mass spectrometric approaches to protein ADP-ribosylation
蛋白质 ADP 核糖基化的质谱方法
- 批准号:
9568790 - 财政年份:2017
- 资助金额:
$ 32.23万 - 项目类别:
Molecular and Biochemical Basis of mTORC1-mediated Feedback Loops
mTORC1 介导的反馈环的分子和生化基础
- 批准号:
9143156 - 财政年份:2015
- 资助金额:
$ 32.23万 - 项目类别:
Molecular and Biochemical Basis of mTORC1-mediated Feedback Loops
mTORC1 介导的反馈环的分子和生化基础
- 批准号:
9341365 - 财政年份:2015
- 资助金额:
$ 32.23万 - 项目类别:
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