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MIT Researchers Discover Programmable DNA-Cutters in Snails


17 October 2023

MIT researchers have uncovered thousands of Fanzors, programmable DNA-cutting enzymes, in various organisms including snails and algae. These RNA-guided enzymes, akin to CRISPR, expand the tools available for genetic research and medical uses. Uniquely found in eukaryotic organisms, Fanzors promise safer and more efficient genome editing.

Scientists from the McGovern Institute for Brain Research at MIT have made an exciting discovery: thousands of programmable DNA-cutting enzymes, dubbed "Fanzors", in a wide array of species ranging from snails to algae. These enzymes, which are similar in function to the bacterial enzymes powering the renowned gene-editing system CRISPR, can be harnessed to specifically target and cut DNA.

The groundbreaking research, published in the journal Science Advances on September 27, points to the potential for a new frontier in genome editing. Unlike CRISPR, which originates from bacterial defense systems, Fanzors are the first known enzymes of this kind found in eukaryotic organisms - a vast group encompassing plants, animals, and fungi. Their eukaryotic origin suggests they might be particularly well-suited for use in human cells and other eukaryotic organisms.

RNA-guided systems, like the one Fanzors are part of, are pivotal in developing programmable tools that are user-friendly. CRISPR's evolution has revolutionized the way researchers manipulate DNA, paving the way for a plethora of experimental gene therapies.

The team's comprehensive genetic database search, orchestrated by lab member Justin Lim, revealed over 3,600 Fanzors across eukaryotes and their associated viruses. This vast number includes five distinct families of the enzymes, highlighting their long evolutionary journey. Interestingly, Fanzors appear to have evolved from bacterial enzymes known as TnpBs, and their transition into eukaryotic cells might have been facilitated by viruses or symbiotic bacteria.

Key experiments led by biological engineering graduate student Kaiyi Jiang showcased Fanzors' unique DNA-targeting abilities, which differ from their bacterial ancestors. When directed to specific sites in the human genome, certain Fanzors exhibited cutting efficiencies ranging between 10 to 20%.

The implications of these findings are significant. Fanzors provide a new platform with a multitude of capabilities. Investigating eukaryotic systems with RNA-guided tools such as Fanzors offers boundless opportunities.

In a nutshell, the original research underscores the widespread presence of programmable RNA-guided DNA nucleases, like Fanzors, in eukaryotes and their associated viruses. The study offers a comprehensive understanding of Fanzors, emphasizing their potential in genome editing and biotechnological applications.

Abstract of the research

Fig. 1. Evolution of Fanzor nucleases and their association with noncoding fRNAs.

Programmable RNA-guided DNA endonucleases are widespread in eukaryotes and their viruses

Abstract: Programmable RNA-guided DNA nucleases perform numerous roles in prokaryotes, but the extent of their spread outside prokaryotes is unclear. Fanzors, the eukaryotic homolog of prokaryotic TnpB proteins, have been detected in genomes of eukaryotes and large viruses, but their activity and functions in eukaryotes remain unknown. Here, we characterize Fanzors as RNA-programmable DNA endonucleases, using biochemical and cellular evidence. We found diverse Fanzors that frequently associate with various eukaryotic transposases. Reconstruction of Fanzors evolution revealed multiple radiations of RuvC-containing TnpB homologs in eukaryotes. Fanzor genes captured introns and proteins acquired nuclear localization signals, indicating extensive, long-term adaptation to functioning in eukaryotic cells. Fanzor nucleases contain a rearranged catalytic site of the RuvC domain, similar to a distinct subset of TnpBs, and lack collateral cleavage activity. We demonstrate that Fanzors can be harnessed for genome editing in human cells, highlighting the potential of these widespread eukaryotic RNA-guided nucleases for biotechnology applications.


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