Journal
SCIENCE
Volume 374, Issue 6563, Pages 57-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abj6856
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Funding
- NSF Integrated Earth Systems [A101357]
- NSF Division of Environmental Biology grant [1950770]
- Department of Energy-Joint Genome Institute [CSP 1675]
- National Library of Medicine
- NIH [1R01-HG009761, 1DP1-HL141201]
- Howard Hughes Medical Institute
- Open Philanthropy Project
- Harold G. and Leila Mathers Foundation
- Poitras Center for Psychiatric Disorders Research at MIT
- Edward Mallinckrodt Jr. Foundation
- Hock E. Tan and K. Lisa Yang Center for Autism Research at MIT
- Yang-Tan Center for Molecular Therapeutics at MIT
- Division Of Environmental Biology
- Direct For Biological Sciences [1950770] Funding Source: National Science Foundation
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IscB and TnpB, proteins encoded in the IS200/IS605 transposons, are likely ancestors of RNA-guided endonucleases Cas9 and Cas12, respectively, using RNA for DNA cleavage. This study unveils a widespread class of transposon-encoded RNA-guided nucleases, OMEGA, with great potential for biotechnological applications.
IscB proteins are putative nucleases encoded in a distinct family of IS200/IS605 transposons and are likely ancestors of the RNA-guided endonuclease Cas9, but the functions of IscB and its interactions with any RNA remain uncharacterized. Using evolutionary analysis, RNA sequencing, and biochemical experiments, we reconstructed the evolution of CRISPR-Cas9 systems from IS200/IS605 transposons. We found that IscB uses a single noncoding RNA for RNA-guided cleavage of double-stranded DNA and can be harnessed for genome editing in human cells. We also demonstrate the RNA-guided nuclease activity of TnpB, another IS200/IS605 transposon-encoded protein and the likely ancestor of Cas12 endonucleases. This work reveals a widespread class of transposon-encoded RNA-guided nucleases, which we name OMEGA (obligate mobile element-guided activity), with strong potential for developing as biotechnologies.
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