Transposable elements, DNA sequences that can move within the genome, pose a significant threat to genome integrity and, consequently, to an organism's viability, particularly when active in the germline. RNA interference (RNAi) pathways, which use small RNAs to silence genes during or after transcription, are a key defense mechanism against these elements. The exoribonuclease MUT-7 is essential for the generation of small RNAs in the germline. While MUT-7 is conserved across species, its function was previously understood only in in flies. Sebastian Falk and his team have discovered that the C-terminal domain of MUT7 (MUT7-C) exists as an individual protein in prokaryotes and has acquired an insertion in animals, thereby expanding its functionality.
First author Virginia Busetto, a postdoc in the Falk lab, explains: “Our findings show that MUT7-C is essential for RNA binding, a role conserved across species, including prokaryotes and humans. However, in worms like Caenorhabditis elegans, it has evolved an insertion necessary to recruit the protein to germ granules.” The team suggests that this dual role highlights, on the one hand its ancient, conserved purpose, and on the other hand specialized adaptations in organisms like C. elegans. While MUT7-C’s insertion facilitates its recruitment to germ granules in worms, the role of similar insertions in humans and other animals remains unclear.
The MUT7 project is part of the Falk lab’s broader effort to decipher the diverse pathways involved in small RNA biogenesis. Group leader Sebastian Falk says: “Although small RNA production has been studied in various organisms, C. elegans stands out because it played a crucial role in the discovery of sRNA gene regulation in the first place. However, its biochemical and structural mechanisms remain poorly understood.” The study employed a combination of experimental structure determination and in silico prediction using AlphaFold, enabling researchers to examine protein evolution across numerous species and uncover the remarkable plasticity of protein structures – insights that were previously constrained by the limited availability of experimentally determined structures.
Transposable elements can create new functions but pose a threat if uncontrolled, leading to an ‘arms race’ between the transposons and the host, with small RNAs playing a crucial role in restricting them. Understanding the molecular and biochemical mechanisms that regulate RNAi is therefore essential. This study benefited from the Falk lab’s long-standing collaboration with the Ketting Lab from the Institute of Molecular Biology Mainz (IMB) in Germany.
DOI: 10.1093/nar/gkae610