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Development of a new CRISPR-Cas3-based tool for large genomic deletions

Objective

The advent of the revolutionary genome editing technique CRISPR-Cas9 has enabled targeted gene mutation, repression, and activation, facilitating impactful biological findings. However, Cas9 as an unbiased DNA deletion tool is limited in its ability to interrogate large regions of DNA of unknown function, because it predominantly generates very small (<20 bp) insertions and deletions at its target site. The capacity to rapidly and efficiently generate large genomic deletions does not currently exist and would be an extremely useful tool for research, allowing for rapid strain engineering of bacterial cells for synthetic biological and metabolic engineering purposes. Additionally, this technology would allow for the interrogation of large segments of non-coding DNA in human cells, much of which has unknown function, but whose variants are often associated with human disease. In this proposal, I aim to develop a Type I-C CRISPR-Cas system employing the Cas3 enzyme (completely distinct from Cas9), which naturally possess coupled nuclease and helicase activity, for high-throughput gene-editing purposes in various prokaryotic, as well as human cells. My preliminary results have shown that this is a credible approach, as I have been able to generate individually, as well as in combination, multiple deletions in bacterial organisms exceeding 60 kb in size. A focal point of the proposal is to adapt this system for use in human cells, which would provide a novel basic research tool with unprecedented capabilities and also could be utilized in human health-related applications. The proposal aims to address this later possibility by utilizing the developed system to treat human cell lines infected with difficult-to-treat pathogenic viruses.
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Coordinator

EUROPEAN MOLECULAR BIOLOGY LABORATORY

Address

Meyerhofstrasse 1
69117 Heidelberg

Germany

Activity type

Research Organisations

EU Contribution

€ 264 669,12

Partners (1)

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THE REGENTS OF THE UNIVERSITY OF CALIFORNIA

Project information

Grant agreement ID: 844093

Status

Ongoing project

  • Start date

    1 July 2019

  • End date

    30 June 2022

Funded under:

H2020-EU.1.3.2.

  • Overall budget:

    € 264 669,12

  • EU contribution

    € 264 669,12

Coordinated by:

EUROPEAN MOLECULAR BIOLOGY LABORATORY

Germany