They have found a way to “program” DNA at will.

The discovery, which was recently published innatureThe programmable “DNA bridge” allows researchers to specify which genetic sequence they want and which DNA molecule they want to insert into the genome, he explains.

“RNA bridging,” says Patrick Hsu, lead author of the article, “is a fundamentally new mechanism for biological programming. Bridge recombination can globally modify genetic material through specific sequence insertion, excision, reversal and more, enabling the ‘word processor’ of the genome.” The neighborhood that goes beyond CRISPR.”

programmable dna

The recombination bridge comes from elements called insertion sequence 110 (IS110), one of countless types of transposable elements, also called “jumping genes,” that clip and paste to change their position within and between microbial genomes. These elements are present in all life forms, and have evolved into professional DNA processing machines, which organisms use to survive. IS110 elements are minimal and consist of a single gene encoding the recombinant enzyme, as well as a series of DNA fragments clustered around it whose function, to date, remains mysterious.

In his lab, Hsu discovered that when IS110 is excised from the genome, the ends of the non-coding DNA come together to produce an RNA molecule (an RNA bridge) that folds into two loops. One of these loops binds to the S110 element itself, while the other binds to the target DNA into which it is inserted. The RNA bridge is the first example of a doubly specific guide molecule.

Each of the two loops of the bridged RNA can be programmed independently, so researchers can mix and match any DNA sequence of interest to the target and donor. This means the system can go beyond its normal function of inserting the IS110 element, and instead allow any desired genetic cargo, such as a functional copy of a defective gene that causes disease, to be inserted anywhere in the genome. In this work, the team demonstrated an efficiency of over 60% in inserting the desired gene into E. coli with a specificity of over 94% for the correct genomic location.

“These programmable RNA bridges,” says Nick Perry, co-author of the study, “distinguish IS110 from other known recombination processes, which lack an RNA component and cannot be programmed.” RNA is a universal power adapter that makes the IS110 compatible with any outlet.”

This discovery complements work conducted in the laboratory of Hiroshi Nishimasu at the University of Tokyo, which was reflected in Article 2: “Nature”. In it, cryogenic electron microscopy was used to determine the molecular structure of the two RNA rings of the recombinant bridge.

According to the researchers, with further research and development, this bridging mechanism promises to be the beginning of a third generation of RNA-guided systems, going beyond the well-known “cut-and-paste” mechanism of CRISPR and so-called RNA interference. (RNI). In fact, a programmable RNA bridge will provide for the first time a unified mechanism that allows the DNA of our genetic inheritance to be rearranged at will.

“This bridging recombination mechanism solves some of the most important challenges facing other genome editing approaches,” says co-author Matthew Doran. “The ability to programmatically rearrange two DNA molecules opens the door to major advances in genome design.”