Protein-primed homopolymer synthesis by an antiviral reverse transcriptase

Stephen Tang, Rimantė Žedaveinytė, Nathaniel Burman, Shishir Pandey, Josephine L. Ramirez, Louie M. Kulber, Tanner Wiegand, Royce A. Wilkinson, Yanzhe Ma, Dennis J. Zhang, George D. Lampe, Mirela Berisa, Marko Jovanovic, Blake Wiedenheft () and Samuel H. Sternberg ()
Additional contact information
Stephen Tang: Columbia University
Rimantė Žedaveinytė: Columbia University
Nathaniel Burman: Montana State University
Shishir Pandey: Montana State University
Josephine L. Ramirez: Columbia University
Louie M. Kulber: Columbia University
Tanner Wiegand: Columbia University
Royce A. Wilkinson: Montana State University
Yanzhe Ma: Columbia University
Dennis J. Zhang: Columbia University
George D. Lampe: Columbia University
Mirela Berisa: Icahn School of Medicine at Mount Sinai
Marko Jovanovic: Columbia University
Blake Wiedenheft: Montana State University
Samuel H. Sternberg: Columbia University

Nature, 2025, vol. 643, issue 8074, 1352-1362

Abstract: Abstract Bacteria defend themselves from viral predation using diverse immune systems, many of which target foreign DNA for degradation1. Defence-associated reverse transcriptase (DRT) systems provide an intriguing counterpoint to this strategy by using DNA synthesis instead2,3. We and others recently showed that DRT2 systems use an RNA template to assemble a de novo gene that encodes the antiviral effector protein Neo4,5. It remains unclear whether similar mechanisms of defence are used by other related DRT families. Here, we show that DRT9 systems defend against phage using DNA homopolymer synthesis. Viral infection triggers polydeoxyadenylate (poly-dA) accumulation in the cell, driving abortive infection and population-level immunity. Cryo-electron microscopy structures reveal how a non-coding RNA serves as both a structural scaffold and reverse transcription template to direct hexameric complex assembly and poly-dA synthesis. Notably, biochemical and functional experiments identify tyrosine residues within the reverse transcriptase itself that probably prime DNA synthesis, leading to the formation of protein–DNA covalent adducts. Synthesis of poly-dA by DRT9 in vivo is regulated by the competing activities of phage-encoded triggers and host-encoded silencers. Collectively, our study identifies a nucleic-acid-driven defence system that expands the paradigm of bacterial immunity and broadens the known functions of reverse transcriptases.

Date: 2025
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DOI: 10.1038/s41586-025-09179-5

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