Protein-primed homopolymer synthesis by an antiviral reverse transcriptase

• 成果类型: Article
• 署名作者: Tang, Stephen; Zedaveinyte, Rimante; Burman, Nathaniel; Pandey, Shishir; Ramirez, Josephine L.; Kulber, Louie M.; Wiegand, Tanner; Wilkinson, Royce A.; Ma, Yanzhe; Zhang, Dennis J.; Lampe, George D.; Berisa, Mirela; Jovanovic, Marko; Wiedenheft, Blake; Sternberg, Samuel H.
• 署名单位: Columbia University; Montana State University System; Montana State University Bozeman; Howard Hughes Medical Institute; Columbia University; Columbia University; Icahn School of Medicine at Mount Sinai; University of Copenhagen
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1600
• DOI: 10.1038/s41586-025-09179-5
• 发表日期: 2025-07-31
• 关键词: cryo-em; sequence; alignment; rna; identification; Visualization; nucleotide; prediction; program; mafft

摘要

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.