Antiviral immunity via telomerase-like reverse transcription in bacteria

Abstract

Defense-associated reverse transcriptases (DRTs) employ diverse and distinctive mechanisms of cDNA synthesis to protect bacteria against viral infection¹. However, the functions and mechanisms of many DRTs remain unknown². Here we identify a new antiviral defense system, DRT10, that associates with a noncoding RNA (ncRNA) to catalyze processive, protein-primed synthesis of tandem-repeat DNA. Reverse transcription is templated by a defined ncRNA region with a characteristic sequence pattern and template boundary elements, both of which are conserved and essential for DNA repeat addition. Cryo-EM reconstructions reveal an unanticipated 2:1 architecture, wherein two RT monomers bind opposite sides of a pseudo-symmetric ncRNA. Biochemical experiments further demonstrate that each RT monomer reverse transcribes the template encoded on its respective side of the ncRNA, but only one generates the long repetitive product, whose template is defined by the distance between two flanking stem-loop anchors. This mode of iterative, boundary-delimited cDNA synthesis exhibits direct parallels to the mechanism of telomeric repeat addition by eukaryotic telomerase, and phylogenetic analyses of RTs across domains of life place telomerase in a monophyletic clade with the DRT family, suggesting a common origin for their DNA polymerization activities. Together with earlier studies of DRT2, DRT3, and DRT9^3–5, our findings identify a conserved mechanistic logic underlying RNA-templated DNA repeat addition across diverse DRTs, despite vastly different architectural solutions, and expand the repertoire of reverse transcription-based strategies for antiviral immunity in bacteria.

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