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The widespread IS200/IS605 transposon family encodes diverse programmable RNA-guided endonucleases
Open accessAbstract
Tracing the origin of CRISPR-Cas: CRISPR-Cas systems have transformed genome editing and other biotechnologies; however, the broader origins and diversity of RNA-guided nucleases have largely remained unexplored. Altae-Tran et al . show that three distinct transposon-encoded proteins, IscB, IsrB, and TnpB, are naturally occurring, reprogrammable RNA-guided DNA nucleases (see the Perspective by Rousset and Sorek). In addition to identifying diverse guide-encoding mechanisms, the authors elucidate the evolutionary relationship between IsrB, IscB, and CRISPR-Cas9. Overall, these newly characterized systems, called OMEGA (for obligate mobile element–guided activity) systems, are found in all domains of life and may be harnessed for biotechnology development. —DJ
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“The IS200/IS605 family of MGEs spreads through “peel-and-paste” transposition catalyzed by the homodimeric transposase TnpA interacting with terminal hairpins at the left end (LE) and right end (RE) of the element.”
From Sequence modeling and design from molecular to genome scale with Evo (2024) · cites this paper as [68]
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“IS605 elements additionally contain an RNA-guided TnpB nuclease and a cognate ωRNA that bias the selfish inheritance of the transposable element (Fig. 4A) (66–69).”
From Sequence modeling and design from molecular to genome scale with Evo (2024) · cites this paper as [68]
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“The discovery of TnpB’s RNA-guided nuclease activity expands the toolkit available for genome editing, particularly in organisms where traditional CRISPR systems may not be as effective.”
From Emerging applications of gene editing technologies for the development of climate-resilient crops (2025) · cites this paper as Altae-Tran et al., 2021
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“[96] Unlike Cas9, IscB possesses approxi-matelytwo-fifthsofitssizebutsharessimilardomainorganization.”
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“In addition, TnpB-encoding genes are among the most abundant genes acrossbacterialand archaeal genomes 32,33 , the activity determinants of TnpB in the natural host have not been explored.”
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“…element-guided activity (OMEGA) systems, were discovered to possess DNA cleavage activity, guided by a noncoding RNA called ωRNA, and are thought to be ancestors of Cas9 and Cas12 effectors from the class 2 clustered regularly interspaced short palindromic repeats (CRISPR) nuclease family 1–3 .”
AI sheds new light on genome editing
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“The Lb dCas12a ancestor protein TnpB has already been characterised ( 73 ) and reprogrammed for genome editing purposes ( 74 ), similarly to the Spy dCas9 ancestor IscB ( 75–77 ).”
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“It is widely thought that type II endonucleases evolved from IscB systems, originating from IS200/IS605 transposons, which contain a small endonuclease (420 – 500 amino acids in length) and a large obligate mobile element guided activity RNA ( ω RNA) 8 .”
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“Because Cas9 and Cas12 evolved independently from different ancestral proteins ( 9 ,10 ), it has been unclear whether Cas12a functions by a similar mechanism (Figure 1 A).”
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“It has recently been shown that TnpB proteins are RNA-guided endonucleases that cleave DNA (49, 50) and are likely the evolutionary predecessors of the Cas12 proteins of class 2 CRISPR-Cas systems (51, 52).”
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“Intriguingly, the IS200/IS605 IS elements, the only IS family with matched spacers by CRISPR-Cas systems in our study, have themselves been recently demonstrated to be programmable RNA-guided nucleases related to the type V CRISPR-Cas system effector (Cas12) (Altae-Tran et al., 2021).”
BackgroundNucleases in gene-editing technologies: past and prologue
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“Among the six IscB candidates, OgeuIscB (496 aa) exhibited varying editing efficiency of up to 4.5% at 28 out of 46 sites in the human genome [199].”
BackgroundInfluentialA Genome-Scale Atlas Reveals Complex Interplay of Transcription and Translation in an Archaeon
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Shelake, R. M., Khalid, M. A., & Kim, J. (2025) · Biotechnology Advances · doi:10.1016/j.biotechadv.2025.108665 · Cited by 14
Viral delivery of an RNA-guided genome editor for transgene-free germline editing in ArabidopsisPreprint
Weiss, T. J., Kamalu, M., Shi, H., Li, Z., Amerasekera, J., Zhong, Z., Adler, B. A., Song, M., Vohra, K., Wirnowski, G., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.07.17.603964 · Cited by 11
Li, W., Liu, S., Fang, X., Zou, J., Jiang, Q., Min, X., Zhu, X., Cao, Y., Gao, X., Han, W., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-67239-w · Cited by 11
Genome editing of medicinal plants: Advances, challenges, and prospects
Chen, W., Shi, Y., Lv, Z., & Chen, W. (2026) · Journal of Integrative Plant Biology · doi:10.1111/jipb.70110 · Cited by 10
Methanotrophic Methanoperedens archaea host diverse and interacting extrachromosomal elements
Shi, L.-D., West-Roberts, J. A., Schoelmerich, M. C., Penev, P. I., Chen, L.-X., Amano, Y., Lei, S., Sachdeva, R., & Banfield, J. F. (2024) · Nature Microbiology · doi:10.1038/s41564-024-01740-8 · Cited by 11
“Unlike Cas12s, which are guided by spacer-derived RNA, TnpB is normally directed by the RNA transcribed from the right end of the transposon 50,51 .”
Antagonistic conflict between transposon-encoded introns and guide RNAs
Žedaveinytė, R., Meers, C., Le, H. C., Mortman, E. E., Tang, S., Lampe, G. D., Pesari, S. R., Gelsinger, D. R., Wiegand, T., & Sternberg, S. H. (2024) · Science · doi:10.1126/science.adm8189 · Cited by 9
CRISPR–Cas systems and applications for crop bioengineering
Uranga, M., Martín‐Hernández, A. M., Storme, N. D., & Pasin, F. (2024) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2024.1483857 · Cited by 11
Evaluation and prediction of guide RNA activities in genome-editing tools
Kim, H. K., & Kim, S. (2025) · Nature Reviews Bioengineering · doi:10.1038/s44222-025-00352-z · Cited by 12
“For instance, protein and RNA engineering led to the development of eIscB-D and eωRNA, which exhibit 20-fold increased activity compared with the wild-type IscB system 62 .”
InfluentialPiotter, E., McClements, M. E., & MacLaren, R. E. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2021.814131 · Cited by 11
“These systems are much smaller, but have lower editing efficiencies and specific PAM requirements (Altae-Tran et al., 2021).”
BackgroundRNA-guided genome engineering: paradigm shift towards transposons
Chang, C.-W., Truong, V. A., Pham, N. N., & Hu, Y. (2024) · Trends in biotechnology · doi:10.1016/j.tibtech.2024.02.006 · Cited by 10
CRISPR beyond: harnessing compact RNA-guided endonucleases for enhanced genome editing
Wang, F., Ma, S., Zhang, S., Ji, Q., & Hu, C. (2024) · Science China Life Sciences · doi:10.1007/s11427-023-2566-8 · Cited by 10
“The IS200/IS605 and IS607 family is characterized by the presence of transposase and nuclease genes flanked by LE and RE elements (Altae-Tran et al., 2021) (Figure 1A).”
InfluentialVaysset, H., Meers, C., Cury, J., Bernheim, A., & Sternberg, S. H. (2025) · Nature Microbiology · doi:10.1038/s41564-024-01889-2 · Cited by 8
“Proteins were clustered at 60% identity and 60% coverage using mmseqs, and representative sequences were aligned using MAFFT L-INS-i 42,44 .”
Discovery of diverse and high-quality mRNA capping enzymes through a language model–enabled platform
Wang, T., Qin, B. R., Li, S. J., Wang, Z., Li, X., Jiang, Y., Qin, C., Ouyang, Q., Lou, C., & Qian, L. (2025) · Science Advances · doi:10.1126/sciadv.adt0402 · Cited by 9
“In addition, because of a lack of sufficient mechanistic or evolutionary understandings, searching by genomic features ( 18 , 19 ) or phylogenetic relations ( 20 ) is barely useful.”
Precise genome editing process and its applications in plants driven by AI
Jiang, B., An, Z., Niu, L., & Qin, D. (2025) · Functional & Integrative Genomics · doi:10.1007/s10142-025-01619-9 · Cited by 9
“Additionally, the nuclease of the OMEGA system is only about 30% the size of Cas9, which gives it a significant advantage in terms of transfection efficiency (Altae-Tran et al. 2021).”
De novo design of potent CRISPR–Cas13 inhibitors
Taveneau, C., Chai, H. X., D’Silva, J., Bamert, R. S., Chen, H., Hayes, B. K., Calvert, R. W., Purcell, J., Curwen, D. J., Munder, F., et al. (2026) · Nature Chemical Biology · doi:10.1038/s41589-025-02136-3 · Cited by 12
“For example, AIcrs could be designed to inhibit CRISPR Cas1–Cas2 acquisition machinery to develop switchable molecular recorders 47 or tailored to regulate emerging classes of editors including TnpB, IsrB, IscB, Fanzor and the numerous CRISPR–Cas-guided DNA integrases 48–50 .”
Improvements in the genetic editing technologies: CRISPR-Cas and beyond
Mingarro, G., & del Olmo, M. (2022) · Gene · doi:10.1016/j.gene.2022.147064 · Cited by 12
LbCas12a mediated suppression of Cotton leaf curl Multan virus
Ashraf, S., Ahmad, A., Khan, S. H., Jamil, A., Sadia, B., & Brown, J. K. (2023) · Frontiers in Plant Science · doi:10.3389/fpls.2023.1233295 · Cited by 9
“Recently, researchers uncovered a new CRISPR-like system in eukaryotes such as OMEGA (Obligate Mobile Element Guided Activity) and Fanzor, that may have broad spectrum applications in eukaryotic gene editing with better efficiency (Altae-Tran et al., 2021; Saito et al., 2023).”
BackgroundFanzor: a compact programmable RNA-guided endonuclease from eukaryotes
Awan, M. J. A., Awan, M. R. A., Amin, I. U., & Mansoor, S. (2023) · Trends in biotechnology · doi:10.1016/j.tibtech.2023.08.003 · Cited by 9
Zhao, D., Gao, X., Zhou, J., Li, J., Qian, Y., Wang, D., Niu, W., Zhang, T., Hu, M., Xiong, H., et al. (2023) · BMC Biology · doi:10.1186/s12915-023-01754-4 · Cited by 9
“To overcome this limitation, the development of domain-inlaid editors is essential and will further enhance the applicability of compact ABEs, including miniBEs such as IscB [2] and TnpB [21].”
BackgroundAdvancement in CRISPR/Cas9 Technology to Better Understand and Treat Neurological Disorders
Datta, A., Sarmah, D., Kaur, H., Chaudhary, A., Vadak, N., Borah, A., Shah, S. V., Wang, X., & Bhattacharya, P. (2022) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-022-01242-3 · Cited by 9
Dunham, D. T., Angermeyer, A., & Seed, K. D. (2023) · Molecular Microbiology · doi:10.1111/mmi.15046 · Cited by 9
Recent advances in genome engineering by CRISPR technology
Lee, Y., Oh, Y., & Lee, S. H. (2024) · BMB Reports · doi:10.5483/bmbrep.2023-0157 · Cited by 10
Chen, Z., Hu, J., Dai, J., Zhou, C., Hua, Y., Hua, X., & Zhao, Y. (2024) · Microbiological Research · doi:10.1016/j.micres.2024.127713 · Cited by 8
Tang, H., Gao, J., Wang, H., Sun, M., Zhang, S., Song, C., & Li, Q. (2025) · Communications Biology · doi:10.1038/s42003-025-07521-1 · Cited by 8
“Previousstudies discovered that the TnpB protein encoded by prokaryotic IS200/IS605 transposons can cleave target DNA under the guidence of RNA and has been utilized for genome editing in human cells 26,27 .”
Mechanisms and engineering of a miniature type V-N CRISPR-Cas12 effector enzyme
Fu, W., Ma, J., Wang, Z., Tang, N., Pan, D., Su, M., Wu, Z., Gan, J., & Ji, Q. (2025) · Nature Communications · doi:10.1038/s41467-025-61290-3 · Cited by 8
Engineered Un1Cas12f1 with boosted gene-editing activity and expanded genomic coverage
Chen, L., Zhou, X., Huang, C., Zhang, Y., Xin, C., Hong, J., & Wang, Y. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2501292122 · Cited by 9
Argonaute-HNH filaments triggered by invader DNA confer bacterial immunity
Kanevskaya, A., Narwal, M., Lisitskaya, L., Moiseenko, A. V., Sokolova, O. S., Sluchanko, N. N., Murakami, K. S., & Kulbachinskiy, A. V. (2025) · Nature Communications · doi:10.1038/s41467-025-66189-7 · Cited by 8
An anti-CRISPR targets the sgRNA to block Cas9 and guides the design of enhanced genome editors
Li, Y., Yin, M., Zhu, Y., Lu, Z., Xiao, B., Zhou, F., Yu, Y., & Huang, Z. (2026) · Nature Structural & Molecular Biology · doi:10.1038/s41594-025-01741-z · Cited by 6
“Recent studies have identified the TnpB proteins from the IS200/ IS605 transposon family as compact ωRNA-guided endonucleases 46,47 .”
Ramasamy, S. P., Rathnasamy, S. A., Sudha, M., Gopalakrishnan, C., Balakrishnan, N., Swaminathan, M., Seshadri, G., & Muthurajan, R. (2025) · Physiological and Molecular Plant Pathology · doi:10.1016/j.pmpp.2025.102640 · Cited by 7
Rauch, B. J., DeLoughery, A., Sper, R. B., Chen, S., Yunanda, S., Masnaghetti, M., Chai, N., Lin, J. C., Neckelmann, A., Bjornson, Y. M., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.01.29.635576 · Cited by 8
Mutational scanning of TnpB reveals latent activity for genome editingPreprint
Thornton, B. W., Weissman, R. F., Rodriguez, J. E., Tran, R. V., Duong, B. C., Terrace, C. I., Nagalakshmi, U., Austin, G., Groover, E. D., Wang, F. Z., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.02.11.637750 · Cited by 8
Shi, S., Yang, G., Yan, Q., Wan, S., Li, M., & Li, M. (2024) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.70051 · Cited by 7
“15,16 By utilizing catalytically de-activated dCas9 protein fused with a transcriptional activator (e.g. p65), the CRISPR/Cas9 system can be engineered to act as a precise transcriptional regulator for target genes through CRISPR activation (CRISPRa).”
BackgroundWu, W., Cui, C., Zhu, Y., Chen, J., Zhuang, Q., Wang, Y., Liu, Z., Gao, H., Ou, G.-Z., Liu, C., et al. (2026) · Cell Research · doi:10.1038/s41422-026-01220-0 · Cited by 9
Metadata
- Authors
- Altae-Tran, H., Kannan, S., Demircioglu, F. E., Oshiro, R., Nety, S. P., McKay, L. J., Dlakić, M., Inskeep, W. P., Makarova, K. S., Macrae, R. K., Koonin, E. V., & Zhang, F.
- Affiliations
- Broad Institute (US)
- Montana State University (US)
- United States National Library of Medicine (US)
- Corresponding author
- Altae-Tran, Han
- Kannan, Soumya
- Zhang, Feng
- ORCID
- Venue
- Science
- Published
- 2021-10
- Volume
- 374
- Issue
- 6563
- Pages
- 57-65
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC8929163
- OpenAlex
- W3198344223
- Cited by
- 407
- References
- 65
- Citations by year
- 2026: 78 · 2025: 92 · 2024: 102 · 2023: 77 · 2022: 42 · 2021: 16
- FWCI
- 18.66
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion)
- Montana State University ScholarWorks (Montana State University) (submittedVersion)
- Funders
- National Science Foundation (1950770)
- U.S. Department of Energy
- Edward Mallinckrodt, Jr. Foundation
- Open Philanthropy Project
- Joint Genome Institute
- National Institutes of Health (5r01hg009761-06, HG009761, 1R01- HG009761)
- National Park Service
- National Heart, Lung, and Blood Institute (DP1HL141201)
- National Human Genome Research Institute (R01-HG009761)
- U.S. National Library of Medicine
- Division of Environmental Biology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- TnpB, RNA-guided endonuclease, genome editing, transposable elements, RNA-guided DNA cleavage
- MeSH terms
- CRISPR-Associated Protein 9, RNA, Guide, CRISPR-Cas Systems, Bacterial Proteins, DNA Transposable Elements, Endodeoxyribonucleases, Genetic Code, Genetic Variation, Conserved Sequence, Evolution, Molecular, RNA, Untranslated, CRISPR-Cas Systems, CRISPR-Associated Proteins
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