Genome instability in cancer: telomeres and DNA repair
癌症中的基因组不稳定性:端粒和 DNA 修复
基本信息
- 批准号:10242700
- 负责人:
- 金额:$ 90.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-02 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:BRCA deficientBiological ModelsCRISPR/Cas technologyCellsChromatin StructureClinicDNA RepairDataDevelopmentDouble Strand Break RepairEpithelial CellsExcisionFunctional disorderGenesGenomeGenomic InstabilityHumanImageMaintenanceMalignant NeoplasmsMicroscopyMolecularPathway interactionsPoly(ADP-ribose) PolymerasesPositioning AttributeResolutionStructureTP53 geneTumor Suppressor ProteinsXCL1 genecancer genomecancer therapyexperimental studygenome editinggenome integritygenome sequencingin vitro Modelinnovationinsightmouse modelnew technologyp53-binding protein 1prognosticpublic health relevancetelomeretumorwhole genome
项目摘要
PROJECT SUMMARY/ABSTRACT
Recent sequencing data has revealed an unanticipated level of genomic instability in cancer. The origin of
these changes is largely unknown. This proposal focuses on two aspects of the maintenance of genome
integrity relevant to cancer: telomere dysfunction and DNA repair. We propose to examine the molecular basis
of the telomere tumor suppressor pathway whereby telomere attrition leads to dysfunctional telomeres and
proliferative arrest. These experiments will make use of normal human epithelial cells in which critical genes
have been removed with CRISPR/Cas9 genome editing and will apply innovative imaging of telomere structure
using super-resolution STORM imaging in combination with expansion microscopy. When the telomere tumor
suppressor pathway fails because of the loss of p53 and Rb, telomeres continue to shorten during early tumor
development, leading to large numbers of dysfunctional telomeres and genome instability (referred to as
telomere crisis). We propose to determine the changes in the genome that result from progression through
telomere crisis. These experiments will involve a new in vitro model for telomere crisis in epithelial cells
combined with whole genome sequencing. Finally, we propose to study the mechanism of double-strand break
(DSB) repair, which is carefully regulated to maintain genome integrity. In particular, we will focus on the
mechanism by which 53BP1 represses the resection of DSBs and promotes their mobility using the mouse
model systems we have developed and new technologies for the analysis of chromatin structure (ATAC
sequencing) and locus position (DamID-LaminB1 marking). These two attributes of 53BP1 are highly relevant
to the induction of lethal genome instability resulting from inhibition of the PARP1 poly(ADP-ribose) polymerase
in BRCA-deficient cells. Collectively, the proposed experiments will illuminate new aspects of genome
instability in cancer. The objective of these studies is to gain insights that will ultimately inform and guide
decisions in the cancer clinic.
项目总结/文摘
项目成果
期刊论文数量(0)
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{{ truncateString('Titia de Lange', 18)}}的其他基金
Genome instability in cancer: telomeres and DNA repair
癌症中的基因组不稳定性:端粒和 DNA 修复
- 批准号:
10736646 - 财政年份:2016
- 资助金额:
$ 90.56万 - 项目类别:
Genome instability in cancer: telomeres and DNA repair
癌症中的基因组不稳定性:端粒和 DNA 修复
- 批准号:
9768895 - 财政年份:2016
- 资助金额:
$ 90.56万 - 项目类别:
Genome instability in cancer: telomeres and DNA repair
癌症中的基因组不稳定性:端粒和 DNA 修复
- 批准号:
10460645 - 财政年份:2016
- 资助金额:
$ 90.56万 - 项目类别:
Genome instability in cancer: telomeres and DNA repair
癌症中的基因组不稳定性:端粒和 DNA 修复
- 批准号:
10006509 - 财政年份:2016
- 资助金额:
$ 90.56万 - 项目类别:
Genome instability in cancer: telomeres and DNA repair
癌症中的基因组不稳定性:端粒和 DNA 修复
- 批准号:
9186655 - 财政年份:2016
- 资助金额:
$ 90.56万 - 项目类别:
The role of telomere-related tetraploidization in cancer
端粒相关四倍体化在癌症中的作用
- 批准号:
8320130 - 财政年份:2011
- 资助金额:
$ 90.56万 - 项目类别:
The role of telomere-related tetraploidization in cancer
端粒相关四倍体化在癌症中的作用
- 批准号:
8680182 - 财政年份:2011
- 资助金额:
$ 90.56万 - 项目类别:
The role of telomere-related tetraploidization in cancer
端粒相关四倍体化在癌症中的作用
- 批准号:
8161963 - 财政年份:2011
- 资助金额:
$ 90.56万 - 项目类别:
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