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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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InfluentialSelf-citationRecent application of CRISPR-Cas12 and OMEGA system for genome editing
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BackgroundInfluentialProgrammable RNA-guided DNA endonucleases are widespread in eukaryotes and their viruses
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“This relationship is supported by phylogenetic analysis of the RuvC-like domains, which indicates independent origins of Cas12s of different type V subtypes from distinct groups of TnpBs ( 6 , 7 ).”
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Self-citationA strategy for Cas13 miniaturization based on the structure and AlphaFold
Zhao, F., Zhang, T., Sun, X., Zhang, X., Chen, L., Wang, H., Li, J., Peng, F., Lai, L., Sui, T., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-41320-8 · Cited by 43
“Cas13bt, EsCas13d, RspCas13d and PspCas13b were obtained from Addgene (#176316, #108303, #108305, and #103862, respectively) 7,16,23 .”
Prado, G. S., Rocha, D. C., dos Santos, L. N., Contiliani, D. F., Nóbile, P. M., Martinati, J. C., Padilha, L., Maluf, M. P., Lubini, G., Pereira, T. C., et al. (2024) · Frontiers in Plant Science · doi:10.3389/fpls.2023.1331258 · Cited by 48
Exploiting viral vectors to deliver genome editing reagents in plants
Shen, Y., Tao, Y., Li, Z., Kimutai, T. H., Song, H., Dong, O. X., & Wan, J. (2024) · aBIOTECH · doi:10.1007/s42994-024-00147-7 · Cited by 41
“Meanwhile, more compact sequence-specific nucleases, such as Cas12f, IscB, and TnpB, are strong candidates to be delivered using virus-based systems (Han Altae-Tran et al. 2021; Karvelis et al. 2021; Siksnys et al. 2020).”
BackgroundEukaryotic RNA-guided endonucleases evolved from a unique clade of bacterial enzymes
Yoon, P. H., Skopintsev, P., Shi, H., Chen, L.-X., Adler, B. A., Al-Shimary, M. J., Craig, R. J., Loi, K. J., DeTurk, E. C., Li, Z., et al. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad1053 · Cited by 36
Engineering IscB to develop highly efficient miniature editing tools in mammalian cells and embryos
Xue, N., Hong, D., Zhang, D., Wang, Q., Zhang, S., Yang, L., Chen, X., Li, Y., Han, H., Hu, C., et al. (2024) · Molecular Cell · doi:10.1016/j.molcel.2024.07.007 · Cited by 45
The Bibliometric Landscape of Gene Editing Innovation and Regulation in the Worldwide
Wei, X., Pu, A., Liu, Q., Hou, Q., Zhang, Y., An, X., Long, Y., Jiang, Y., Dong, Z., Wu, S., et al. (2022) · Cells · doi:10.3390/cells11172682 · Cited by 39
Engineered IscB–ωRNA system with expanded target range for base editing
Xiao, Q., Li, G., Han, D., Wang, H., Yao, M., Ma, T., Zhou, J., Zhang, Y., Zhang, X., He, B., et al. (2024) · Nature Chemical Biology · doi:10.1038/s41589-024-01706-1 · Cited by 41
“This is similar to a previous study showing that OgeuIscB exhibited indel activity with a guide containing a spacer length of 14–26 nt 17 .”
Developments and prospects for doubled haploid wheat
Eliby, S., Беккужина, С. С., Kishchenko, O., Iskakova, G., Kylyshbayeva, G., Jatayev, S., Soole, K. L., Langridge, P., Borisjuk, N. V., & Shavrukov, Y. N. (2022) · Biotechnology Advances · doi:10.1016/j.biotechadv.2022.108007 · Cited by 38
Molecular basis and engineering of miniature Cas12f with C-rich PAM specificity
Su, M., Li, F., Wang, Y., Gao, Y., Lan, W., Shao, Z., Zhu, C., Tang, N., Gan, J., Wu, Z., et al. (2023) · Nature Chemical Biology · doi:10.1038/s41589-023-01420-4 · Cited by 38
“However, most of these compact nucleases exhibit only low or minimal genome editing capacity in mammalian cells in their natural forms 11,23,27,28,31 .”
TnpB homologues exapted from transposons are RNA-guided transcription factors
Wiegand, T., Hoffmann, F. T., Walker, M. W. G., Tang, S., Richard, E., Le, H. C., Meers, C., & Sternberg, S. H. (2024) · Nature · doi:10.1038/s41586-024-07598-4 · Cited by 37
The transposon-encoded protein TnpB processes its own mRNA into ωRNA for guided nuclease activity
Nety, S. P., Altae-Tran, H., Kannan, S., Demircioglu, F. E., Faure, G., Hirano, S., Mears, K., Zhang, Y., Macrae, R. K., & Zhang, F. (2023) · The CRISPR Journal · doi:10.1089/crispr.2023.0015 · Cited by 35
“The limited TAM diversity of TnpBs may be explained by the co-evolution of TnpA and TnpB, as TnpA also utilizes the TAM to recognize the transposon ssDNA for excision and insertion.(1,2,6,43,52) Although it is not yet clear how, if at all, TnpB interacts with TnpA and the transposon DNA, the fact that both proteins po…”
BackgroundMethodInfluentialThe type V effectors for CRISPR/Cas-mediated genome engineering in plants
Zhang, R., Chai, N., Liu, T., Zheng, Z., Lin, Q., Xie, X., Wen, J., Yang, Z. F., Liu, Y., & Zhu, Q. (2024) · Biotechnology Advances · doi:10.1016/j.biotechadv.2024.108382 · Cited by 36
TadA reprogramming to generate potent miniature base editors with high precision
Zhang, S., Song, L., Yuan, B., Zhang, C., Cao, J., Chen, J., Qiu, J., Tai, Y., Chen, J., Qiu, Z., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-36004-2 · Cited by 40
CRISPR-assisted transcription activation by phase-separation proteins
Liu, J., Chen, Y., Nong, B., Luo, X., Cui, K., Li, Z., Zhang, P., Tan, W., Yang, Y., Ma, W., et al. (2023) · Protein & Cell · doi:10.1093/procel/pwad013 · Cited by 37
“It is conceivable that if SpCas9 is further replaced with smaller Cas proteins such as IscB (Kapitonov et al., 2015; Altae-Tran et al., 2021; Schuler et al., 2022) and Cas12f (Xu et al., 2021b), the resulting fusion proteins along with the gRNA may be packaged into a single vector (e.g.,…”
BackgroundEngineering miniature IscB nickase for robust base editing with broad targeting range
Han, L., Hu, Y., Mo, Q., Yang, H., Gu, F., Bai, F., Sun, Y., & Ma, H. (2024) · Nature Chemical Biology · doi:10.1038/s41589-024-01670-w · Cited by 40
“The TAM of OgeuIscB was characterized to be NWRRNA (W represents A or T, and R represents A or G) by a biochemical TAM screen assay 22,24 .”
Assessing and engineering the IscB–ωRNA system for programmed genome editing
Yan, H., Tan, X., Zou, S., Sun, Y., Ke, A., & Tang, W. (2024) · Nature Chemical Biology · doi:10.1038/s41589-024-01669-3 · Cited by 36
“Identified in the human gut metagenome, OgeuIscB–ωRNA has been reported to generate double-stranded breaks (DSBs) in mammalian cells 2 .”
InfluentialApplication of CRISPR/Cas-based gene-editing for developing better banana
Tripathi, L., Ntui, V. O., & Tripathi, J. N. (2024) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2024.1395772 · Cited by 42
Effective genome editing with an enhanced ISDra2 TnpB system and deep learning-predicted ωRNAs
Marquart, K. F., Mathis, N., Mollaysa, A., Müller, S., Kissling, L., Rothgangl, T., Schmidheini, L., Kulcsár, P. I., Allam, A., Kaufmann, M. M., et al. (2024) · Nature Methods · doi:10.1038/s41592-024-02418-z · Cited by 41
“IscB and TnpB proteins are typically more compact than Cas9 and Cas12 endonucleases 4 and are guided by RNA species derived from the transposon right-end (RE) element to bind and cleave substrate DNA 4,5 .”
Coral holobionts and biotechnology: from Blue Economy to coral reef conservation
van de Water, J. A. J. M., Tignat‐Perrier, R., Allemand, D., & Ferrier‐Pagès, C. (2021) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2021.10.013 · Cited by 36
Evolution-guided protein design of IscB for persistent epigenome editing in vivo
Kannan, S., Altae-Tran, H., Zhu, S., Xu, P., Strebinger, D., Oshiro, R., Faure, G., Moeller, L., Pham, J., Mears, K. S., et al. (2025) · Nature Biotechnology · doi:10.1038/s41587-025-02655-3 · Cited by 40
“OMEGA–IscB, the ancestor of Cas9 14 , is a particularly compelling candidate for genome and epigenome editing due to its small size (~300–550 amino acids (aa)), which renders it more conducive to delivery via adeno-associated viruses (AAVs); its dual nuclease composition, which enables control over…”
InfluentialSelf-citationRecent advances in CRISPR-based single-nucleotide fidelity diagnostics
Kohabir, K. A. V., Sistermans, E. A., & Wolthuis, R. M. F. (2025) · Communications Medicine · doi:10.1038/s43856-025-00933-4 · Cited by 39
Language Modeling Materializes a World Model of Protein BiologyPreprint
Candido, S., Hayes, T., Derry, A., Rao, R., Lin, Z., Verkuil, R., Wu, B. Z., Lee, J. S., Bruguera, E. S., Keval, J. A., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.06.03.729735 · Cited by 85
Compact Cas9d and HEARO enzymes for genome editing discovered from uncultivated microbes
Goltsman, D. S. A., Alexander, L. M., Lin, J., Ocampo, R. F., Freeman, B., Lamothe, R. C., Rivas, A. P., Temoche-Diaz, M. M., Chadha, S., Nordenfelt, N. S., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-35257-7 · Cited by 37
Mechanistic and evolutionary insights into a type V-M CRISPR–Cas effector enzyme
Omura, S. N., Nakagawa, R., Südfeld, C., Warren, R. V., Wu, W. Y., Hirano, H., Laffeber, C., Kusakizako, T., Kise, Y., Lebbink, J. H. G., et al. (2023) · Nature Structural & Molecular Biology · doi:10.1038/s41594-023-01042-3 · Cited by 33
Advances in the application of CRISPR-Cas technology in rapid detection of pathogen nucleic acid
Li, X., Zhong, J., Li, H., Qiao, Y., Mao, X., Fan, H., Zhong, Y., İmani, S., Zheng, S., & Li, J. (2023) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2023.1260883 · Cited by 36
“It won the fi rst of Nature ’ s fi ve most in fl uential scienti fi c events in the past 10 years and the Nobel Prize in Chemistry in 2020 (Makarova et al., 2020; Altae-Tran et al., 2021).”
Harnessing artificial intelligence to advance CRISPR-based genome editing technologies
Thomson, T., Li, G. L., Strilchuk, A. W., Cui, H., Wang, B., & Li, B. (2025) · Nature Reviews Genetics · doi:10.1038/s41576-025-00907-1 · Cited by 34
“Recently discovered ancestral Cas-related proteins, such as the transposon-encoded TnpB and IscB nucleases, which use an associated ωRNA for target recognition, are emerging as programmable genome editing tools 28–30 .”
Structure and engineering of miniature Acidibacillus sulfuroxidans Cas12f1
Wu, Z., Liu, D., Pan, D. Y., Yu, H., Shi, J. F., Ma, J., Fu, W., Wang, Z., Zheng, Z., Qu, Y., et al. (2023) · Nature Catalysis · doi:10.1038/s41929-023-00995-4 · Cited by 33
CRISPR-Cas Technology: Emerging Applications in Clinical Microbiology and Infectious Diseases
Serajian, S., Ahmadpour, E., Oliveira, S. M. R., Pereira, M. D. L., & Heidarzadeh, S. (2021) · Pharmaceuticals · doi:10.3390/ph14111171 · Cited by 35
“[147] -CRISPR enzyme’s ancestors reported in microbes [148,149]”
BackgroundPromoter editing for the genetic improvement of crops
Shi, L., Su, J., Cho, M., Song, H., Dong, O. X., Liang, Y., & Zhang, Z. (2023) · Journal of Experimental Botany · doi:10.1093/jxb/erad175 · Cited by 36
Modularity and diversity of target selectors in Tn7 transposons
Faure, G., Saito, M., Benler, S., Peng, I., Wolf, Y. I., Strecker, J., Altae-Tran, H., Neumann, E. N., Li, D., Makarova, K. S., et al. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.05.013 · Cited by 30
Self-citationDNA on the move: mechanisms, functions and applications of transposable elements
Schmitz, M., & Querques, I. (2023) · FEBS Open Bio · doi:10.1002/2211-5463.13743 · Cited by 41
“Strikingly, adaptive immunity relying on CRISPR-Cas systems in prokaryotes and the V(D)J recombination pathway in vertebrates, have arisen independently via domestication of recombinases encoded by unrelated TEs [26 – 28].”
BackgroundFoley, N. M., Harris, A. J., Bredemeyer, K. R., Ruedi, M., Puechmaille, S. J., Teeling, E. C., Criscitiello, M. F., & Murphy, W. J. (2024) · Cell Genomics · doi:10.1016/j.xgen.2023.100482 · Cited by 31
Bio–Nano Toolbox for Precision Alzheimer's Disease Gene Therapy
Liu, Y., Xia, X., Zheng, M., & Shi, B. (2024) · Advanced Materials · doi:10.1002/adma.202314354 · Cited by 31
Genome editing in plants using the TnpB transposase system
Li, Q., Wang, Y., Hou, Z., Zong, H., Wang, X., Zhang, Y. E., Wang, H., Chen, H., Wang, W., & Duan, K. (2024) · aBIOTECH · doi:10.1007/s42994-024-00172-6 · Cited by 31
“The class 2 CRISPR effectors Cas9 and Cas12 may have evolved, independently, from an ancestral TnpB-like nuclease, which is still commonly found in insertion sequences (ISs) of the IS200/IS605 and IS607 families of transposons (Altae-Tran et al. 2021; Kapitonov et al. 2016).”
BackgroundAragonés, V., Aliaga, F., Pasin, F., & Daròs, J. (2022) · Biotechnology Journal · doi:10.1002/biot.202100504 · Cited by 29
CRISPR/Cas-mediated germplasm improvement and new strategies for crop protection
Dong, G., & Fan, Z. (2024) · Crop Health · doi:10.1007/s44297-023-00020-x · Cited by 30
“The OMEGA effector TnpB is the putative ancestor of Cas12, suggesting that TnpB may also be the ancestor of the Fanzor (Fz) protein encoded by eukaryotic trans-posons [43].”
Engineering a New Generation of Gene Editors: Integrating Synthetic Biology and AI Innovations
Chia, B. S., Seah, S., Wang, B., Shen, K., Srivastava, D., & Chew, W. L. (2025) · ACS Synthetic Biology · doi:10.1021/acssynbio.4c00686 · Cited by 31
Recruitment of Mobile Genetic Elements for Diverse Cellular Functions in Prokaryotes
Benler, S., & Koonin, E. V. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.821197 · Cited by 28
“…while Cas9 was derived from a transposon-encoded nuclease IscB in a single evolutionary event (Kapitonov et al., 2016; Altae-Tran et al., 2021), Cas12 apparently evolved from transposon nucleases of the TnpB family on multiple, independent occasions (Faure et al., 2019; Altae-Tran et al., 2021).”
BackgroundInfluentialSelf-citationMini-PE, a prime editor with compact Cas9 and truncated reverse transcriptase
Lan, T., Chen, H., Tang, C., Wei, Y., Liu, Y., Zhou, J., Zhuang, Z., Zhang, Q., Chen, M., Zhou, X., et al. (2023) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2023.08.018 · Cited by 29
Miniature CRISPR-Cas12 Systems: Mechanisms, Engineering, and Genome Editing Applications
Tang, N., & Ji, Q. (2024) · ACS Chemical Biology · doi:10.1021/acschembio.4c00247 · Cited by 25
CRISPR-Cas, Argonaute proteins and the emerging landscape of amplification-free diagnostics
Santiago‐Frangos, A., Nemudryi, A. A., Nemudraia, A., Wiegand, T., Nichols, J. E., Krishna, P., Scherffius, A. M., Zahl, T., Wilkinson, R. A., & Wiedenheft, B. (2022) · Methods · doi:10.1016/j.ymeth.2022.06.002 · Cited by 26
“Recently, TnpB proteins, the evolutionary precursors to Cas12, have been shown to be RNAguided DNA-binding proteins with collateral nuclease activity [47,48].”
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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