Molecular mechanisms of memory formation and tolerance in CRISPR-Cas systems
CRISPR-Cas系统中记忆形成和耐受的分子机制
基本信息
- 批准号:10570544
- 负责人:
- 金额:$ 12.5万
- 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
- 起止时间:2023-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:Adaptive Immune SystemAffectArchaeaAutoimmunityBacteriaBacterial GenomeBacteriophagesBiochemicalBiochemistryBioinformaticsBiologyBiophysicsCRISPR/Cas technologyCellsCharacteristicsClassificationClustered Regularly Interspaced Short Palindromic RepeatsCommunicationComplexDNADNA RepairDNA SequenceDNA-Directed RNA PolymeraseDataDevelopmentElementsEngineeringEnvironmentGenesGeneticGenetic TranscriptionGenomeGenomicsGoalsHealthHumanImmune responseImmune systemImmunityImmunologic MemoryImpairmentInfectionIntegraseIntegration Host FactorsInvadedLaboratoriesLinkLocationMediatingMemoryMentorshipMobile Genetic ElementsMolecularMolecular BiologyNucleic AcidsOutcomePathogenicityPhysiologicalPlasmidsPopulationProcessRNAResearchResearch DesignRibosomal RNARoleSiteStaphylococcus epidermidisSystemTestingTranscriptTransfer RNAUniversitiesWorkWritingbiological systemscareercold shock proteincostds-DNAexperimental studyfitnessgenome editinggenome wide screengenotoxicityimprovedinsightmemory acquisitionmolecular diagnosticsnucleasepreventpromoterrecruitrecurrent infectionskillstechnology developmenttool
项目摘要
Project Summary
CRISPR-Cas are prokaryotic adaptive immune systems that protect bacteria and archaea from invading mobile
genetic elements, such as phages and plasmids. CRISPR-Cas systems acquire immunological memories during
infection by integrating short fragments from the invader’s genome into the CRISPR locus of the host. These
fragments, called “spacers”, are later transcribed into CRISPR RNAs that are loaded on Cas nucleases and
guide them to recognize and cleave infecting nucleic acids. Depending on their genetic composition, CRISPR-
Cas systems are classified into six types (I-VI). While spacer acquisition has been extensively studied in type I
and II systems, type III systems are just now starting to be explored. The overall goal of this application is to
define the molecular mechanisms that govern spacer acquisition by the prevalent, yet less studied, type III-A
CRISPR-Cas system, and understand its implications during CRISPR-Cas defense and tolerance. Preliminary
work on the type III-A system of Staphylococcus epidermidis revealed that this system preferentially acquires
new spacers by two independent modes. The first mode acquires spacers from some, but not all, highly
transcribed genes, and spans their entire transcribed region. The first aim of this proposal is to elucidate how
the acquisition machinery recognizes specific genes as substrates for preferential acquisition. This will be
achieved by dissecting the DNA sequences that recruit the spacer-integrase complex to specific genes, finding
host factors that mediate gene-specific spacer acquisition, and test for the physiological relevance of this process
during the CRISPR-Cas immune response. The second mode of acquisition by the type III-A system is similar
to the previously studied type I and II systems, where spacers are acquired from free dsDNA ends at the bacterial
chromosomal terminus, in a manner that is dependent on the cell’s DNA-repair machinery. Such self-targeting
spacers are expected to induce autoimmunity and be negatively selected, however we found them to be stably
fixed in the bacterial population, suggesting the existence of unknown mechanisms that inhibit targeting by Cas
nucleases at this site, thus preventing CRISPR autoimmunity. The second aim of this proposal will define the
genomic context that allows self-targeting spacers to be tolerated, analyze the temporal dynamics of CRISPR-
Cas immunity at free DNA ends, and explore the genetic components needed for CRISPR-tolerance and
accumulation of self-targeting spacers. This proposed work will not only transform our conceptual understanding
of the spacer acquisition process, but also could lead to CRISPR-based technological developments in molecular
biology and diagnostics. To achieve these goals, I have assembled a team of experts in the fields of transcription,
DNA repair, bioinformatics, biochemistry and biophysics. Their guidance, along with the continued mentorship
of Prof. Luciano Marraffini and the scientific environment of the Rockefeller University, will allow me to perform
the proposed research, as well as to develop writing, mentorship and communication skills, that will support my
successful transition to an independent career.
项目总结
项目成果
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