piRNA processing by a trimeric Schlafen-domain nuclease

Nadezda Podvalnaya, Alfred W. Bronkhorst, Raffael Lichtenberger, Svenja Hellmann, Emily Nischwitz, Torben Falk, Emil Karaulanov, Falk Butter, Sebastian Falk () and René F. Ketting ()
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Nadezda Podvalnaya: Institute of Molecular Biology
Alfred W. Bronkhorst: Institute of Molecular Biology
Raffael Lichtenberger: Vienna Biocenter Campus (VBC)
Svenja Hellmann: Institute of Molecular Biology
Emily Nischwitz: Epigenetics & Genome Stability
Torben Falk: Vienna Biocenter Campus (VBC)
Emil Karaulanov: Institute of Molecular Biology
Falk Butter: University of Vienna
Sebastian Falk: Vienna Biocenter Campus (VBC)
René F. Ketting: Institute of Molecular Biology

Nature, 2023, vol. 622, issue 7982, 402-409

Abstract: Abstract Transposable elements are genomic parasites that expand within and spread between genomes1. PIWI proteins control transposon activity, notably in the germline2,3. These proteins recognize their targets through small RNA co-factors named PIWI-interacting RNAs (piRNAs), making piRNA biogenesis a key specificity-determining step in this crucial genome immunity system. Although the processing of piRNA precursors is an essential step in this process, many of the molecular details remain unclear. Here, we identify an endoribonuclease, precursor of 21U RNA 5′-end cleavage holoenzyme (PUCH), that initiates piRNA processing in the nematode Caenorhabditis elegans. Genetic and biochemical studies show that PUCH, a trimer of Schlafen-like-domain proteins (SLFL proteins), executes 5′-end piRNA precursor cleavage. PUCH-mediated processing strictly requires a 7-methyl-G cap (m7G-cap) and a uracil at position three. We also demonstrate how PUCH interacts with PETISCO, a complex that binds to piRNA precursors4, and that this interaction enhances piRNA production in vivo. The identification of PUCH concludes the search for the 5′-end piRNA biogenesis factor in C. elegans and uncovers a type of RNA endonuclease formed by three SLFL proteins. Mammalian Schlafen (SLFN) genes have been associated with immunity5, exposing a molecular link between immune responses in mammals and deeply conserved RNA-based mechanisms that control transposable elements.

Date: 2023
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DOI: 10.1038/s41586-023-06588-2

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