New gene-editing technique can ‘turn on’ enzymes that cause DNA base mutations

Targeted mutations to the genome can now be introduced by splitting specific mutator enzymes and then triggering them to reconstitute, according to research from the Perelman School of Medicine. Led by graduate student Kiara Berríos under the supervision of Rahul Kohli, an associate professor of infectious diseases, and Junwei Shi, an assistant professor of cancer biology, the investigations uncovered a novel gene editing technique that offers superior control compared to other existing techniques and has the potential to be used in-vivo. The technique has been patented, and the research is published in Nature Chemical Biology.

DNA helix with a piece being removed by a surgeon’s glove with scissors.

Base editors are one of the latest and most effective ways to achieve precise gene editing. In DNA targeted by base editors, C:G base pairs in DNA can be mutated to T:A or A:T base pairs can be turned to G:C. The base editors use CRISPR-Cas proteins to locate a specific DNA target and DNA deaminase enzymes to modify and mutate the target. Nevertheless, there was no way to trigger mutations at specific times or keep the editor in check to prevent undesired mutations.

The Penn researchers find that DNA deaminases can be divided into two inactive pieces, which can then be put back together using a small cell-permeable molecule called rapamycin. The new split-engineered base editors system can be introduced and lay dormant within a cell until the small molecule is added, at which point the base editing complex can be rapidly “turned on” to alter the genome.

Read more at Penn Medicine News.