Novel Rad18 functions in Histone Modification and Regulation of Gene Expression
Rad18 在组蛋白修饰和基因表达调节中的新功能
基本信息
- 批准号:8683787
- 负责人:
- 金额:$ 20.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-09-19 至 2016-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressBiological MarkersBone MarrowCancer BiologyCell DeathCell physiologyCellsChromatinCoupledDNA DamageDNA RepairDNA Repair PathwayDNA biosynthesisDNA lesionDNA repair proteinDataDetectionDevelopmentDouble Strand Break RepairEarly identificationEnvironmentEnvironmental ExposureEpigenetic ProcessEtiologyEventExposure toGene ExpressionGene Expression RegulationGene TargetingGenesGeneticGenetic TranscriptionGenomeGenome StabilityGenomic InstabilityGoalsHistone H2AHistonesHumanIndividualIonizing radiationKnowledgeMaintenanceMalignant NeoplasmsMediatingMissionMono-SMusMutagensNormal CellNuclearOutcomePathway interactionsPatientsPhysiologicalPlayPredispositionPublic HealthRadiationRadiation therapyRadioresistanceRecruitment ActivityResearchResistanceRoleSignal TransductionSomatic CellStem cellsTestingTherapeuticTranscriptional RegulationTumor SuppressionUbiquitinationWorkaryl hydrocarbonsbasecancer cellcancer therapycarcinogenesischemotherapeutic agentchemotherapychromatin modificationenvironment related cancerenvironmental carcinogenesisepigenomegene repressiongenome-widegenotoxicityhistone modificationimprovedin vivoinnovationkillingsmutantneoplasticneoplastic cellnovelpreventpublic health relevancerepairedresponsesmall moleculeubiquitin-protein ligase
项目摘要
DESCRIPTION (provided by applicant): There are major gaps in our understanding of how DNA damage is sensed and repaired and how DNA repair is coordinated with other dynamic chromatin functions (e.g. transcription, DNA replication) to maintain genome stability. DNA repair prevents environmentally-induced cancer in normal cells and can confer resistance to chemotherapy and radiotherapy in cancer cells. Therefore, knowledge of genome maintenance mechanisms is crucial for us to understand, prevent, and successfully treat cancer. The immediate objective of the proposed exploratory project is to define a new role for the DNA repair protein Rad18 in chromatin modification and regulation of gene expression. Our long-term goal is to determine how Rad18-mediated regulation of gene expression contributes to genome maintenance and tumor suppression (in normal cells) and chemo/radio-resistance (in cancer cells). Previously, Rad18 has been implicated only in regulating DNA repair proteins. Based on strong preliminary data, the central hypothesis is that direct mono-ubiquitination of Histone H2A at K119 by Rad18 is a novel mechanism for transcriptional repression that contributes to genome maintenance. The rationale is that defining mechanisms of Rad18-mediated genome maintenance will provide a better understanding of environmental carcinogenesis and new opportunities for improving cancer therapy. The Specific Aims (SAs) of this exploratory R21 proposal are: (1) Define novel Rad18 functions in epigenetic control of gene expression. (2) Identify Rad18-responsive histone marks and transcriptional events in vivo. For SA1 we will perform genome-wide analyses to identify Rad18-dependent histone marks associated with altered gene expression following exposure to environmental and therapeutic genotoxic agents (Polycyclic Aryl Hydrocarbons, or PAH, and Ionizing Radiation respectively) in primary human cells. SA2 will determine the extent to which Rad18 influences gene expression and histone modifications in bone marrow (BM) progenitor cells, known targets of genotoxicity from environmental PAH and radiotherapy. To determine the contribution of H2A-ubiquitination to Rad18-mediated genome maintenance we will use 'separation-of-function' Rad18 mutant specifically lacking H2A-directed E3 ligase activity. The proposed ideas and research are innovative because they seek to provide new paradigms where none exist: chromatin modification by Rad18 is novel and indicates that Rad18 may have new genome maintenance functions involving transcriptional repression. The proposed mouse studies are innovative because physiological Rad18 functions in genome maintenance have not previously been studied in BM progenitor cells (or other somatic cells) in vivo. The work is significant because it
will define new Rad18 functions that protect normal cells against environmental exposures, and confer resistance to chemotherapy and radiotherapy in cancer cells. This work will identify new biomarkers of environmental and therapeutic genotoxicity. We seek to validate Rad18 and its effectors as druggable targets whose inhibition sensitizes cancer cells to chemotherapy and radiation.
描述(由申请人提供):我们对DNA损伤如何被感知和修复以及DNA修复如何与其他动态染色质功能(例如转录、DNA复制)协调以维持基因组稳定性的理解存在重大差距。DNA修复可以防止正常细胞中环境诱导的癌症,并可以使癌细胞对化疗和放疗产生抗性。因此,基因组维持机制的知识对于我们理解、预防和成功治疗癌症至关重要。该项目的近期目标是确定DNA修复蛋白Rad 18在染色质修饰和基因表达调控中的新作用。我们的长期目标是确定Rad 18介导的基因表达调控如何有助于基因组维持和肿瘤抑制(在正常细胞中)和化疗/放射抗性(在癌细胞中)。以前,Rad 18仅涉及调节DNA修复蛋白。基于强有力的初步数据,中心假设是Rad 18在K119处对组蛋白H2 A的直接单泛素化是有助于基因组维持的转录抑制的新机制。其基本原理是,定义Rad 18介导的基因组维持机制将提供更好地了解环境致癌作用和改善癌症治疗的新机会。这个探索性的R21提案的具体目标(SA)是:(1)定义新的Rad 18功能在基因表达的表观遗传控制。(2)识别Rad 18响应性组蛋白标记和体内转录事件。对于SA 1,我们将进行全基因组分析,以确定与原代人类细胞暴露于环境和治疗遗传毒性剂(分别为多环芳烃或PAH和电离辐射)后基因表达改变相关的Rad 18依赖性组蛋白标记。SA 2将确定Rad 18影响骨髓(BM)祖细胞中基因表达和组蛋白修饰的程度,骨髓祖细胞是环境PAH和放疗遗传毒性的已知靶点。为了确定H2 A-泛素化对Rad 18介导的基因组维持的贡献,我们将使用特异性缺乏H2 A-指导的E3连接酶活性的“功能分离”Rad 18突变体。提出的想法和研究是创新的,因为他们试图提供新的范例,其中没有存在:染色质修饰Rad 18是新颖的,并表明Rad 18可能有新的基因组维护功能,涉及转录抑制。提出的小鼠研究是创新的,因为生理学Rad 18功能的基因组维护以前没有研究过在骨髓祖细胞(或其他体细胞)在体内。这项工作意义重大,因为它
将定义新的Rad 18功能,保护正常细胞免受环境暴露,并赋予癌细胞对化疗和放疗的抵抗力。这项工作将确定环境和治疗遗传毒性的新生物标志物。我们试图验证Rad 18及其效应物作为可药用靶点,其抑制使癌细胞对化疗和放疗敏感。
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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Cyrus Vaziri其他文献
Cyrus Vaziri的其他文献
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