Abstract
All eukaryotes, including yeast, plants, animals and humans, possess linear chromosomes. The conserved eukaryotic telomere-telomerase systems, originated and evolved over 1 billion years, protect the chromosomal ends and regulate critical physiological functions through complex networks. In this study, we replace the endogenous eukaryotic telomeres in the single-chromosome yeast Saccharomyces cerevisiae with the prokaryotic telomere system TelN/tos from the Escherichia phage N15, which forms a closed hairpin structure, by interrupting the MRX/Sae2 pathway. The prokaryotic telomeres effectively protect linear chromosomal ends and prevent genetic instability. Through adaptive evolution, we identify yeast strains harboring additional mutations (TEL1 and CYR1) that restore functional MRX/Sae2 activity, thereby improving host fitness and meiotic capacity. Interestingly, the two-associated TelN/tos telomeres position deeper into chromosomes and exhibit increased interactions with their adjacent regions. The successful replacement of a complex eukaryotic chromosomal telomere with a simple bacteriophage system demonstrates functional equivalence between these divergent systems, implying possible natural origins of such stochasticity (e.g., horizontal gene transfers). Furthermore, these engineered strains facilitate development of a tos-YAC system that enabled iterative assembly and stable maintenance of megabase-level heterogeneous DNA (1.23-2.77 Mb), providing a robust platform for large-scale DNA manipulation.
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Acknowledgments
We thank Yanxia Mai and Zhiping Zhang from the core facility center of CAS Center for Excellence in Molecular Plant Science, and Chuan Wang from Gene Read Tech, for technical help.
Funding
This research was supported by grants from National Natural Science Foundation of China with grant numbers 31921006 (Z.Q.), 32022045(X.X.), 31770099(X.X.), 31830105(Z.Q.), 32271474(Y.S.), National Key Research and Development Program of China with grant numbers 2023YFA0913700 (X.X.), 2018YFA0903700 (Z.Q.), Shanghai Municipal Science and Technology Major Project (Z.Q., X.X.), the Science and Technology Commission of Shanghai Municipality 23HC1400300 (P.F.), and Zhejiang Provincial Science Fund for Distinguished Young Scholars LR23C060001 (Y.S.).
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Fan Zhou is an employee and shareholder of Gene Read Tech. The remaining authors declare no competing interests.
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Deng, W., Li, Y., Shao, Y. et al. Engineering yeast chromosomal telomeres with a bacteriophage system. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73335-2
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DOI: https://doi.org/10.1038/s41467-026-73335-2
