Structural basis of antiphage defence by an ATPase-associated reverse transcriptase

Jerrin Thomas George, Nathaniel Burman, Royce A. Wilkinson, Senuri de Silva, Quynh McKelvey-Pham, Murat Buyukyoruk, Adelaide Dale, Hannah Landman, Ava B. Graham, Steven Z. DeLuca and Blake Wiedenheft ()
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Jerrin Thomas George: Department of Microbiology and Cell Biology
Nathaniel Burman: Department of Microbiology and Cell Biology
Royce A. Wilkinson: Department of Microbiology and Cell Biology
Senuri de Silva: Department of Microbiology and Cell Biology
Quynh McKelvey-Pham: Department of Microbiology and Cell Biology
Murat Buyukyoruk: Department of Microbiology and Cell Biology
Adelaide Dale: Department of Microbiology and Cell Biology
Hannah Landman: Department of Microbiology and Cell Biology
Ava B. Graham: Department of Microbiology and Cell Biology
Steven Z. DeLuca: Department of Microbiology and Cell Biology
Blake Wiedenheft: Department of Microbiology and Cell Biology

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Reverse transcriptases (RTs) have well-established roles in the replication and spread of retroviruses and retrotransposons. However, recent evidence suggests that RTs have been conscripted by cells for diverse roles in antiviral defence. Here we determine structures of a type I-A retron, which explain how RNA, DNA, RT, HNH-nuclease and four molecules of a structure maintenance of chromosome (SMC)-family ATPase assemble into a 364 kDa complex that provides phage defence. We show that phage-encoded nucleases trigger degradation of the retron-associated DNA, leading to activation of the HNH nuclease. The HNH nuclease cleaves tRNASer, stalling protein synthesis and arresting viral replication. Taken together, these data reveal diverse and paradoxical roles for RTs in the perpetuation and elimination of genetic parasites.

Date: 2025
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DOI: 10.1038/s41467-025-63285-6

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