No CRISPR: oddball ‘jumping gene’ enzyme edits genomes without breaking DNA
A molecular peculiarity discovered in bacteria might have the potential to revolutionize genome manipulation by allowing scientists to add, remove, or rearrange large DNA segments.
The method, detailed in three recent papers published in Nature and Nature Communications, leverages the natural phenomenon of mobile genetic elements known as jumping genes to integrate into genomes.
Operated by an RNA molecule called a ‘bridge’ RNA or ‘seekRNA’, this system has successfully edited genes in bacterial and test-tube settings. However, its adaptability to function in human cells remains uncertain. If it proves effective, it could be groundbreaking due to its compact size and capacity to facilitate substantial genetic alterations, much larger than what is achievable with the CRISPR–Cas9 gene-editing system, all without damaging the DNA.
Sandro Fernandes Ataide, a structural biologist at the University of Sydney and an author of the Nature Communications paper, believes that if this technique can be applied to other cells, it will be transformative, introducing a new era in gene editing.
Transposable treasures
Despite CRISPR–Cas9’s popularity and capabilities, it is primarily suited for modifying small portions of genomes rather than enabling versatile cut-and-paste operations, as some media reports imply. The technique commonly alters one or a few DNA bases, necessitating DNA breakage and relying on the cell’s DNA repair mechanisms to implement the desired modifications, risking unintended genetic changes during repair processes.
Researchers, as CRISPR advances into human medicine, are keen to diversify the genome-editing toolbox to introduce entire genes or multiple genes at targeted sites. This enhanced capability could lead to developing therapies addressing multiple mutations within a single gene and engineering immune cells to combat cancer through various avenues while maintaining precise gene insertion control in the genome.
Patrick Hsu, a bioengineer at the Arc Institute, emphasizes the necessity of designing entire genome sections rather than individual bases for future genetic manipulations.
To uncover potential tools, Hsu and his team explored a class of enzymes facilitating the movement of mobile DNA elements in bacteria, focusing on a group of transposable elements known as IS110. These enzymes exhibit a unique RNA-based targeting system, with one end of the RNA linking to the DNA segment for insertion and the other end binding to the genomic location for placement. By manipulating the RNA sequences at both ends, researchers programmed IS110 enzymes to insert specific DNA segments into desired genome sites, showcasing precise DNA segment insertion and extraction from the Escherichia coli bacterium’s genome.
Elizabeth Kellogg from St. Jude Children’s Research Hospital commends the programmable and site-specific nature of transposable elements like IS110, highlighting the challenge in achieving such precision with other transposition systems requiring several proteins.
The study of IS110 and IS1111 mechanisms represents a significant achievement, whereas other genome-editing methods often necessitate multiple proteins for large genetic alterations. The IS110 and IS1111 systems require just one protein, significantly smaller than the Cas enzymes in CRISPR systems, a critical factor in medical applications, considering the limited cargo capacity of viruses frequently employed for transporting genome-editing components into human cells.
While the IS110 family enzymes currently exhibit suboptimal performance in mammalian cells, ongoing efforts aim to enhance their efficacy in such cellular systems. Despite this, the IS110 mechanism demonstrates a unique and elegant method by which mobile DNA elements traverse the genome, promising novel insights for genome-editing tool development.
As Mother Nature provides an array of solutions, the exploration of novel mechanisms holds promise for the future of genetic manipulation.
