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  • Coordinated RNA- and protein-templated synthesis of double-stranded DNA by a dual reverse transcriptase immune system. Cell Wang, M., Yoneyama, K., Žedaveinytė, R., Ishikawa, J., Tang, S., Le, H. C., Wiegand, T., Ramirez, J. L., Nagahata, N., Ma, Y., Zhang, D. J., Helmeczi, E., Berisa, M., Jovanovic, M., Hiraizumi, M., Yamashita, K., Nishimasu, H., Sternberg, S. H. 2026

    Abstract

    Defense-associated reverse transcriptase (DRT) systems mediate antiviral immunity through distinct modes of cDNA synthesis: class 1 DRTs catalyze untemplated synthesis, whereas class 2 DRTs polymerize non-coding RNA-templated products. However, how these distinct modes drive defense remains unclear. Here, we report that DRT3 immunity arises when class 1 and class 2 RT activities cooperate to produce self-complementary double-stranded DNA (dsDNA). DRT3a uses a 5'-ACACAC-3' RNA template to synthesize poly-(dTdG) repeats, whereas DRT3b synthesizes poly-(dCdA) repeats without any nucleic acid template. Cryo-electron microscopy reveals that DRT3b forms a hexamer and uses active-site-adjacent residues as deoxyadenosine and deoxycytidine gates to enforce alternating nucleotide addition, representing a unique example of amino-acid-templated DNA polymerization. DRT3 is toxic in cells lacking RecBCD, implicating host recombination machinery in limiting dsDNA accumulation, and the phage-encoded RecBCD inhibitor Gam triggers DRT3-mediated abortive infection. These findings reveal how two polymerases with distinct templating strategies generate complementary DNA for antiviral defense.

    View details for DOI 10.1016/j.cell.2026.07.012

    View details for PubMedID 42520802

https://orcid.org/0009-0000-0876-939X