New gene-editing technique offers scientists ability to 'turn on' enzymes that cause DNA base mutations

3D-model DNA Credit: Michael Strck/Wikimedia/ GNU Free Documentation License
According to research at the Perelman school of medicine at the University of Pennsylvania, targeted mutations can be introduced to the genome by breaking specific mutator enzymes. This triggers them to reconstitute. Under the guidance of Rahul Kohli (MD, Ph.D.), an associate professor at Penn of Infectious Diseases, and Junwei Shi (Assistant professor of Cancer Biology), Kiara Berros, a graduate student, discovered a novel method for gene editing that is more controllable than other methods and can be used in-vivo. The research has been published in Nature Chemical Biology's latest issue.

Base editors are the most efficient and effective way to accomplish precise gene editing. Base editors can modify DNA to target specific C:G base pair pairs. However, it was impossible to cause mutations at certain times or to keep the editor under control to prevent undesirable mutations.

Researchers at Penn discovered that DNA deaminases can now be broken down into two inactive parts. These can then be reassembled using a small, cell-permeable molecule called Rapamycin. The new split-engineered bases editors (seBEs), can be introduced into cells and left there until the small molecule is added. At that point, the base editing system can be quickly "turned on" to alter genome.

Kohli stated that the newly-created split-engineered base editors offer new possibilities for research and therapeutics. We can control when mutations occur so that these seBEs could be used in vivo to model disease by altering a gene. This is similar to how scientists control gene knockouts. Clinicians may one day have the ability to edit a patient's gene for treatment purposes.

Shi stated that "Splitting DNA Deaminase" can work without base editors. Shi said that this technique could be used to control genetic mutations that can cause cancer growth and development. It could also be used for identifying vulnerabilities in cancer cells.

Kohli's laboratory and Shi's lab plan to continue this research by applying controllable gene editing to cell-based screening research and adding spatial control to go along with temporal control. The strength of the researchers' approach to base editing is that the controllable split enzyme can be combined with other developments in CRISPR/Cas, which is rapidly expanding.

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Kiara N. Berros and colleagues, Controllable genome editing using split-engineered base editor, Nature Chemical Biology (2021). Information from Nature Chemical Biology Kiara N. Berros and colleagues, Controllable genome edit with split-engineered bases editors, (2021). DOI: 10.1038/s41589-021-00880-w