Study employs engineered base editors for controllable genome editing

According to a recent study from the Perelman School of Medicine at the University of Pennsylvania, targeted mutations to the genome can be instituted by splitting specific mutator enzymes and later inducing them to reconstitute.

Study employs engineered base editors for controllable genome editing
Image Credit: Penn Medicine: Perelman School of Medicine–University of Pennsylvania.

The research was headed by graduate student Kiara Berríos under the supervision of Rahul Kohli MD, Ph.D., an associate professor of Infectious Diseases at Penn, and Junwei Shi Ph.D., an assistant professor of Cancer Biology. The analyses unraveled a new gene-editing process that provides better control when compared to other techniques present to date. This has the potential to be used in-vivo and is also patented.

The study was published in the Nature Chemical Biology journal.

Accurate gene editing can be achieved with base editors, one of the latest and most efficient ways. In the case of DNA targeted by base editors, A:T base pairs can be mutated to G:C or C:G base pairs can be turned to T:A or. The base editors employ CRISPR-Cas proteins to identify a specific DNA target and DNA deaminase enzymes to alter and mutate the target.

However, there is no means to induce mutations at precise times or restrain the editor in check to stop undesired mutations.

Researchers from Penn discovered that DNA deaminases can be segregated into two inactive pieces, which can be combined later with a small cell-permeable molecule named rapamycin. The novel split-engineered base editors (seBEs) system can be inserted and will be dormant inside a cell until the small molecule is introduced. At this juncture, the base editing complex can be quickly “turned on” to modify the genome.

Our newly created split-engineered base editors really offer new potential for both research and therapeutics. Since we can control the time mutations are made, there is a possibility to use these seBEs in vivo to model diseases by altering a gene, similar to how scientists control the timing of gene knockouts, and even potentially someday offer clinicians the ability to control editing of a patient’s genes for treatment purposes.”

Rahul Kohli, Associate Professor, Infectious Diseases, Perelman School of Medicine, University of Pennsylvania

Shi states, “Splitting DNA deaminase can also work outside of base editors. As a cancer researcher, I see this technique as having potential in controlling genetic changes that cause cancer development and growth. It could also be used to identify vulnerabilities in cancer cells.”

Kohli’s and Shi’s laboratories intend to continue this research by implementing controllable genome editing to cell-based screen research and by introducing a layer of spatial control to assist temporal control. A positive of this approach is that the controllable split enzyme system can be combined with other new advances in the fast-expanding CRISPR/Cas field to newly gain regulatory control over the numerous base editing strategies.

Source:
Journal reference:

Berríos, K. N., et al. (2021) Controllable genome editing with split-engineered base editors. Nature Chemical Biology. doi.org/10.1038/s41589-021-00880-w.

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