DNA Protein Cross-Links:Cellular Effects and Repair Mechanisms
DNA 蛋白质交联:细胞效应和修复机制
基本信息
- 批准号:10626876
- 负责人:
- 金额:$ 53.57万
- 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:2014-05-21 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAffectAffinityAgingAntineoplastic AgentsBindingBiologicalBiological AssayBiological ProcessBypassCandidate Disease GeneCell DeathCell SurvivalCell physiologyCellsChemicalsChromatinCisplatinDNADNA RepairDNA Repair GeneDNA SequenceDNA biosynthesisDNA lesionDNA mappingDNA replication forkDNA-Protein InteractionDNA-protein crosslinkDiseaseEmbryoEnvironmental PollutantsExcisionExcision RepairExposure toFailureFundingGamma RaysGeneticGenetic RecombinationGenetic TranscriptionGenomeGenomic InstabilityGenomic SegmentGerm-Line MutationGoalsHistonesHumanIn VitroIncidenceIonizing radiationLesionLinkLipid PeroxidationMalignant NeoplasmsMass Spectrum AnalysisMechlorethamineMetabolismMethodsMolecularMusNucleotide Excision RepairOccupationalOutcomePathologyPathway interactionsPatientsPeptide HydrolasesPeptidesPrecipitationPredispositionPrimary carcinoma of the liver cellsProcessProgeriaProteinsProteolytic ProcessingProteomicsRad30 proteinReactive Oxygen SpeciesResearchRoleSiteStructureSyndromeSystemTimeToxic Environmental SubstancesToxic effectTransition ElementsUltraviolet RaysXenobioticsXenopusadductadverse outcomeage relatedantitumor drugchromosome replicationcrosslinkdemethylationearly onsetenvironmental agenterythritol anhydrideexperimental studygenome integritygenotoxicityhuman DNAmolecular modelingnext generation sequencingrecruitrepairedtumorigenesis
项目摘要
Project Summary
DNA-protein cross-links (DPCs) are formed when proteins become covalently bound to DNA form
spontaneously as a result of normal cellular processes such as lipid peroxidation, histone demethylation, DNA
replication, transcription, and DNA repair. DPCs can be induced by exposure to anti-tumor drugs, transition
metals, UV light, and γ-radiation. DPCs interfere with many biological processes and are implicated in the
accelerated aging and increased cancer incidence observed in Ruijs-Aalfs syndrome patients. The goal of this
application is to map DPC lesions along the genome, investigate how human cells recognize and remove
these exceedingly bulky DPC lesions, and to identify the mechanisms by which they cause mutagenicity and
cell death. Our central hypothesis is that unrepaired DPCs compromise the efficiency and accuracy of DNA
replication and contribute to the toxicity and mutagenicity induced by the agents listed above. Our research
plan focuses on three aims. First, will use next generation sequencing in combination with affinity pull down
and protein precipitation to identify specific genomic regions susceptible to spontaneous and xenobiotic-
induced DPC formation in human cells. Second, we will elucidate the role of proteolytic processing in DPC
repair. Affinity capture, unbiased searches, and candidate gene-based approaches twill be used to identify
proteins required for proteolytic processing and repair of DPCs, determine how cells convert DPCs to smaller
peptide lesions (DpCs), and identity critical DNA repair proteins required for DPC removal from the genome.
Third, we will investigate the effects of DPCs and DpCs on DNA replication. Our in vitro studies using DNA Pol
η showed that efficiency and fidelity of translesion synthesis past peptide DpCs is strongly dependent on DNA
sequence context. We will examine the effects of sequence context on bypass efficiency and mutagenicity in
human cells. The structural basis for the context effects on the efficiency and fidelity of bypass will be studied
by molecular modeling and NMR studies. We will use a newly developed assay that employs pigyBac
transposition of DpC or DPC containing DNA to examine the effects these lesions have on chromosome
replication. These studies will for the first time examine the biological outcomes of structurally defined
chromosomal DPCs in human cells.
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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{{ truncateString('COLIN R CAMPBELL', 18)}}的其他基金
DNA Protein Cross-Links:Cellular Effects and Repair Mechanisms
DNA 蛋白质交联:细胞效应和修复机制
- 批准号:
10428509 - 财政年份:2014
- 资助金额:
$ 53.57万 - 项目类别:
DNA-Protein cross-links: cellular effects and repair mechanisms
DNA-蛋白质交联:细胞效应和修复机制
- 批准号:
8759022 - 财政年份:2014
- 资助金额:
$ 53.57万 - 项目类别:
DNA Protein Cross-Links:Cellular Effects and Repair Mechanisms
DNA 蛋白质交联:细胞效应和修复机制
- 批准号:
9816926 - 财政年份:2014
- 资助金额:
$ 53.57万 - 项目类别:
DNA Protein Cross-Links:Cellular Effects and Repair Mechanisms
DNA 蛋白质交联:细胞效应和修复机制
- 批准号:
10017995 - 财政年份:2014
- 资助金额:
$ 53.57万 - 项目类别:
DNA Protein Cross-Links:Cellular Effects and Repair Mechanisms
DNA 蛋白质交联:细胞效应和修复机制
- 批准号:
10713474 - 财政年份:2014
- 资助金额:
$ 53.57万 - 项目类别:
DNA-Protein cross-links: cellular effects and repair mechanisms
DNA-蛋白质交联:细胞效应和修复机制
- 批准号:
9441806 - 财政年份:2014
- 资助金额:
$ 53.57万 - 项目类别:
DNA Protein Cross-Links:Cellular Effects and Repair Mechanisms
DNA 蛋白质交联:细胞效应和修复机制
- 批准号:
10163054 - 财政年份:2014
- 资助金额:
$ 53.57万 - 项目类别:
Summer Research Training at the University of Minnesota Medical School
明尼苏达大学医学院暑期研究培训
- 批准号:
7802239 - 财政年份:2007
- 资助金额:
$ 53.57万 - 项目类别:
Summer Research at the University of Minnesota Medical School
明尼苏达大学医学院暑期研究
- 批准号:
10418721 - 财政年份:2007
- 资助金额:
$ 53.57万 - 项目类别:
Summer Research Training at the University of Minnesota Medical School
明尼苏达大学医学院暑期研究培训
- 批准号:
8066443 - 财政年份:2007
- 资助金额:
$ 53.57万 - 项目类别:
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