Mapping the Cellular Responses to DNA Double-Strand Breaks Using On-Demand CRISPR technologies and High-resolution Fluorescence Microscopy
Mapping the Cellular Responses to DNA Double-Strand Breaks Using On-Demand CRISPR technologies and High-resolution Fluorescence Microscopy
批准号:
10715720
负责人:
Yang Liu
金额:
$38.5万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-08-01 至 2028-05-31
关键词:
AccelerationAddressAgingBindingBiochemicalCRISPR/Cas technologyCellsCellular StressChromatinChromosomal translocationComplementComplexDNADNA DamageDNA Double Strand BreakDNA RepairDNA Repair GeneDefectDevelopmentDiseaseDouble Strand Break RepairFluorescence MicroscopyGene MutationGenetic ResearchGenetic TranscriptionGenomeHumanHuman GenomeImmune systemInnate Immune SystemKineticsKnowledgeLinkMaintenanceMalignant NeoplasmsMammalian CellMapsMediatingMutationNuclearPathway interactionsProteinsResearchResearch ProposalsResolutionRoleSignal TransductionStructureTestingTubeVisualizationbiophysical techniquesenvironmental stressorgenetic approachgenome integritygenomic locusgenotoxicityhuman diseaseinsightnovelprogramsrapid detectionrepairedresponsespatiotemporaltemporal measurement
中文摘要
人类基因组的完整性不断受到挑战
英文摘要
The integrity of the human genome is constantly challenged by
environmental and cellular stresses, resulting in various DNA damage and gene
mutations. Many proteins have evolved to rapidly detect, signal, and repair DNA
damage inside living cells, forming an orchestrated network known as DNA
damage response (DDR). Unsurprisingly, DDR defects, such as DNA repair protein
mutations, are often linked to human diseases, including developmental
abnormalities, accelerated aging, and common cancers. The past decades of
biochemical and genetic research have generated a wealth of knowledge
regarding the identities of DDR factors, their roles in genome maintenance, and
how they contribute to the diseases when they go awry. However, the detailed
spatiotemporal parameters by which DDR factors mediate DNA repair remain
largely elusive. What timescales do DDR factors search for and bind to damaged
DNA in living cells? Do DDR factors form specific structures to facilitate an
accurate repair? How does DNA damage regulate other nuclear DNA activities,
such as transcription? This research program aims to address these fundamental
questions by investigating DDR dynamics during DNA double-strand break (DSB)
repair. DSB is one of the most genotoxic DNA damage types frequently occurring
in our bodies. Recently, we have established an experimental platform that allows
quantitative visualization of DDR factors and on-demand DSB induction at specific
genomic loci and with a second-scale temporal resolution, a capability achieved
by marrying high-resolution fluorescence microscopy with the very fast
(vf)CRISPR technique pioneered by our lab. Here, we will take full advantage of
this novel platform and comprehensively map the DSB-induced dynamics of DDR
factors, chromosome translocation, and activities of transcription and cGAS in
single human cells. This study will strongly complement DSB repair research
conventionally performed in test tubes and at the ensemble level, providing
valuable mechanistic insights into DSB repair with unprecedented resolutions.
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