DNA double-strand break repair, chromosome translocations and cancer
DNA双链断裂修复、染色体易位和癌症
基本信息
- 批准号:10394193
- 负责人:
- 金额:$ 174.71万
- 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:2014-04-08 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalATM deficientActinsAddressAffectAutomobile DrivingBRCA1 geneBiochemistryCell CycleCell Cycle StageCell NucleusCellular biologyChromatinChromosomal RearrangementChromosomal translocationChromosomesCollaborationsComplexComputational BiologyComputer AnalysisDNADNA AdductsDNA DamageDNA Double Strand BreakDNA RepairDNA Repair PathwayDNA SequenceDNA TopoisomerasesDNA biosynthesisDNA lesionDNA replication forkDataDefectDevelopmentDouble Strand Break RepairEtiologyExcisionExperimental NeoplasmsFundingGenesGeneticGenomeGenomic InstabilityGenomic SegmentGenomic approachGenomicsGoalsHumanImmunoglobulinsLesionLightLymphocyteLymphomaMalignant NeoplasmsMammalian CellMapsMolecular AnalysisMutateMutationMutation AnalysisNatureNuclearOutcomePathogenicityPathologicPathway interactionsPatternPhasePhosphotransferasesPhysiologicalPoisoningProcessProteinsRecording of previous eventsRepetitive SequenceReplication ErrorRibosomal DNASignal PathwaySignal TransductionSingle-Stranded DNASourceT-Cell ReceptorTechnologyTopoisomeraseTopoisomerase InhibitorsTransactTumor Suppressor ProteinsWiskott-Aldrich SyndromeYeast Model SystemYeastscancer genomecancer typecell typechemotherapeutic agentchemotherapyclinically relevantexperimental analysisgenome editinggenotoxicityin vivomouse modelnext generationprogramsrepairedresponsestressortelomeretumortumorigenesistumorigenic
项目摘要
The genetic lesions that promote tumorigenesis, including chromosomal rearrangements, are generated
primarily by illegitimate DNA repair. In this renewal application, we will continue to investigate the pathological
consequences of aberrant DNA double-strand break (DSB) repair. This highly collaborative and integrated
program will elucidate how DNA sequence, chromatin accessibility and nuclear organization influence the fate
and pathological outcomes of DSBs in a cell type and cell cycle dependent manner. We will continue to use a
combination of genetics in yeast and mouse models, biochemistry and cell biology. The application of next
generation technologies together with high-throughput genomics approaches provides an unprecedented wealth
of information about genomic instability in cancer genomes. We propose to leverage our multifaceted
experimental approach with the strong genomics and computational biology components that pervade the
Program. Drs. Rabadan and Baer will study mutation signatures - the statistically enriched patterns of DNA
substitutions and rearrangements common across tumors - associated with specific BRCA1 deficiencies. They
will also characterize mutation signatures generated by the other three Projects. Collectively these data will help
deconvolute the complex mutational landscape of human tumors. Drs. Symington and Ciccia will address the
nature of the initiating DNA lesions resulting in chromosome rearrangements, focusing on DNA replication errors
in repair-deficient yeast and genome-edited mammalian cells. Dr. Sha will connect chromatin accessibility, locally
and globally, with its propensity to break and yield translocations; pathological translocations at the
immunoglobulin and T cell receptor loci during lymphocyte maturation fuel lymphoma development. Specifically,
Dr. Zha will elucidate how ATM deficiencies favor translocations in a cell type and cell cycle dependent manner.
Finally, Drs. Gautier and Gottesman will study how the spatial organization of the nucleus modulates DNA repair.
Specifically, they will determine how nuclear actin and WASP, the gene mutated in Wiskott-Aldrich Syndrome,
enables resection and influences chromosome translocations following DSBs or genotoxic lesions triggered by
topoisomerase inhibition. The four Projects will be supported by two scientific Cores. All leaders and co-leaders
have a strong history and record of productive collaboration.
促进肿瘤发生的遗传病变,包括染色体重排
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JEAN GAUTIER其他文献
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{{ truncateString('JEAN GAUTIER', 18)}}的其他基金
DNA Repair and Genomic Instability in Cancer Development and Therapy
癌症发展和治疗中的 DNA 修复和基因组不稳定性
- 批准号:
10221625 - 财政年份:2015
- 资助金额:
$ 174.71万 - 项目类别:
DNA Repair and Genomic Instability in Cancer Development and Therapy
癌症发展和治疗中的 DNA 修复和基因组不稳定性
- 批准号:
9322608 - 财政年份:2015
- 资助金额:
$ 174.71万 - 项目类别:
DNA Repair and Genomic Instability in Cancer Development and Therapy
癌症发展和治疗中的 DNA 修复和基因组不稳定性
- 批准号:
9979776 - 财政年份:2015
- 资助金额:
$ 174.71万 - 项目类别:
DNA Repair and Genomic Instability in Cancer Development and Therapy
癌症发展和治疗中的 DNA 修复和基因组不稳定性
- 批准号:
8955897 - 财政年份:2015
- 资助金额:
$ 174.71万 - 项目类别:
DNA Repair and Genomic Instability in Cancer Development and Therapy
癌症发展和治疗中的 DNA 修复和基因组不稳定性
- 批准号:
9117526 - 财政年份:2015
- 资助金额:
$ 174.71万 - 项目类别:
DNA double-strand break repair, chromosomes translocations and cancer
DNA 双链断裂修复、染色体易位和癌症
- 批准号:
8835071 - 财政年份:2014
- 资助金额:
$ 174.71万 - 项目类别:
DNA double-strand break repair, chromosomes translocations and cancer
DNA 双链断裂修复、染色体易位和癌症
- 批准号:
9241973 - 财政年份:2014
- 资助金额:
$ 174.71万 - 项目类别:
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