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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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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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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Additional file 1 of Eukaryotic-driven directed evolution of Cas9 nucleases
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Additional file 2 of Eukaryotic-driven directed evolution of Cas9 nucleases
Ruta, G. V., Ciciani, M., Kheir, E., Gentile, M. D., Amistadi, S., Casini, A., & Cereseto, A. (2024) · Figshare · doi:10.6084/m9.figshare.26697431
Additional file 3 of Eukaryotic-driven directed evolution of Cas9 nucleases
Ruta, G. V., Ciciani, M., Kheir, E., Gentile, M. D., Amistadi, S., Casini, A., & Cereseto, A. (2024) · Figshare · doi:10.6084/m9.figshare.26697434
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Mutant‐Initiated Structure‐Guided Refinement Enables Second‐Generation Compact IscB Genome Editors
Sha, T., Zhao, D., Zhao, X., Lu, Y., Wang, R., Liu, J., Li, Y., Li, S., Chen, M., Bi, C., et al. (2026) · ChemBioChem · doi:10.1002/cbic.70392
“IscB is a hypercompact (~400 aa) RNA-guided endonuclease encoded by IS200/IS605-family transposons and considered an evolutionary precursor of type V CRISPR systems [12, 15].”
CRISPR and Fanzor in sickle cell disease: current progress and future prospects
Humoudi, A. Y. A., Alotaibi, A. G., Alosaimi, N. F., Alshalani, A., Alqahtani, S. D., Alsaab, S. M., Almutiri, B. J., & Albariqi, M. M. H. (2026) · Frontiers in Genome Editing · doi:10.3389/fgeed.2026.1774014
Pen, N., Guo, Q., Wang, Y. Z., Xiong, B., Xu, B., Yang, J., ZHANG, Y., Fan, Z., Ren, W., Ling, G., et al. (2026) · Research Square · doi:10.21203/rs.3.rs-9485642/v1
Gene Editing Technologies for Hereditary Hearing Loss: Prospects and Challenges
Wang, M., Wang, B., Yang, M., Tan, F., Qi, J., & Chai, R. (2026) · Neuroscience Bulletin · doi:10.1007/s12264-026-01651-0 · Cited by 1
Jiao, X., Chen, W., Lv, Z., & Chen, W. (2026) · Engineering in Life Sciences · doi:10.48130/els-0026-0001
Xavier, T. S., Simão, F. A., Rosa, H. D. S., Colomer, J. C. S., Cohen, R. W. F., Folescu, T. W., Carvalho-Assef, A. P. D., Leão, R. S., & Marques, E. A. (2026) · Current Microbiology · doi:10.1007/s00284-026-04994-z
“Members of the IS200/IS605 family are described as genomic hotspots for the capture of “passenger genes” and site-specific rearrangements [42 , 43 ], which may facilitate horizontal transfer and the dissemination of resistance in clinical settings [ 44 ].”
Guo, Q., Shen, Q., Zhao, L., Zhou, X., Yan, S., Xue, Y., & Zheng, Y. (2026) · Biotechnology and Bioengineering · doi:10.1002/bit.70281
Structure basis for single-strand nucleic acid targeting by IscB and variants
Xu, C., Yang, Q., Niu, X., & Ke, A. (2026) · Nucleic Acids Research · doi:10.1093/nar/gkag607
“It is considered the evolutionary ancestor of the CRISPR-associated effector Cas9 [ 1–3 ].”
InfluentialZhang, W., Hu, J., Li, R., Sheng, D., Yue, X., She, Q., Zhang, Y., Li, Y., Li, Z., & Wu, C. (2026) · Nature Communications · doi:10.1038/s41467-026-74908-x
“Supporting spectroscopic data for all isolated compounds are provided in Supplementary Figs 28 – 72.”
Genome editing for aquaculture breeding: established applications and emerging directions
Wu, Y. N., Yang, L., Zhang, Y., Wu, M., Huang, S., Guo, X., Wang, D., Xu, J., & Zhou, L. J. (2026) · Water Biology and Security · doi:10.1016/j.watbs.2026.100683
Structure‐ and deep learning–guided engineering of a size‐minimized CRISPR /Cas
Le, S., & Thach, T. T. (2026) · FEBS Journal · doi:10.1111/febs.70707
Compact 9dBEs Enable Efficient and Precise Genome Editing in Mammalian Cells and In Vivo
Xiao, Q., Tian, Z., Weng, L., Xu, K., Han, D., Wu, Z., Li, J., Li, S., Zhang, Q., Zhao, X., et al. (2026) · Advanced Science · doi:10.1002/advs.77279
“For each specific PAM, frequencies occurring more than once were retained and the log fold change (logFC) of these retained PAMs was calculated as the log ratio compared to the non-target control, with a 1e-9 pseudocount adjustment [ 19 ].”
A New Beginning of Rational Design in the Age of Large Language Models of Synthetic Biology
Li, L., Wang, Z., He, X., & Lou, C. (2026) · International Conference on Bioinformatics and Intelligent Computing (BIC) · doi:10.1145/3809986.3810000
“A prominent example is the discovery of OMEGA (obligate mobile element-guided activity) systems [ 3 , 4 ] .”
Oh, Y., Jeon, S., Gwon, L. W., Sim, B., & Lee, S. H. (2026) · Nucleic Acids Research · doi:10.1093/nar/gkag849
“Among the recently characterized RNA-guided nucleases, OMEGA-TnpB (hereafter referred to as TnpB) is a transposon-derived effector encoded by insertion sequence (IS) elements that has emerged as a promising platform owing to its potential applicability in genome engineering [ 14 , 15 ].”
When Homing Endonuclease Meets Transposon: The OMEGA System
Kojima, K. K. (2026) · Biology · doi:10.3390/biology15171491
Ullah, I., Ahmad, N., Bhat, A. H., Hussain, A., Wei, F., & Hongzhi, W. (2026) · Plant Cell Reports · doi:10.1007/s00299-026-03965-9
“Given its smaller molecule size, more streamlined structure, and lower cargo, TnpB has proven to be a useful alternative editing platform in crops where delivery of large Cas proteins is technically difficult (Altae-Tran et al. 2021; Shen et al. 2025).”
3D Genome Engineering Using CRISPR/dCas Systems
Mamaeva, N. Y., Yakovlev, V. A., Kristovskiy, N. V., Feskin, P. G., Vinnikov, R. S., Oleinikov, P. D., Shmakov, S., Шайтан, К. В., Kirpichnikov, M. P., & Shaytan, A. К. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27188104
“Recently characterized miniature DNA-targeting systems—including minimal Cas12 [118], TnpB and IscB [119], and Fanzors [120]—as well as RNA-targeting systems such as Cas13e [121,122], are generally much smaller than conventional effectors such as SpCas9.”
Wang, R., Liu, H., Jia, S., Bai, S., Cao, X., Li, D., & Sun, Y. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.09.09.750255
De novo-engineered guide RNA-directed transposition with TnpB-family proteins
Schargel, R. D., Machado, L. C., Kumaran, S., Thesier, J., Krishnan, S. S., Guarné, A., & Peters, J. E. (2026) · Molecular Cell · doi:10.1016/j.molcel.2026.08.023 · Cited by 3
A viral origin for RNA-guided immunity
Bravo, J. P. K. (2026) · Science · doi:10.1126/science.ael0758
Ma, B., Li, Y., Zhang, D., Wu, Y., Gao, J., Li, H., & Jia, S. (2026) · Frontiers in Genome Editing · doi:10.3389/fgeed.2026.1945303
García-Tenorio, E. M., Alvarez, M., Richard, E., & Desviat, L. R. (2026) · Methods in molecular biology · doi:10.1007/978-1-0716-5547-4_3
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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