Retrotransposons are mobile genetic elements that, once transcribed, are capable of self-driven re-integration at various genomic sites through reverse transcription (retrotransposition), with consequences to genomic variation and stability. Retrotransposons constitute a considerable proportion of the human genome. Although most of these elements have lost the ability to retrotranspose, some, including 80–100 copies of long interspersed element-1 (LINE-1), remain active. How LINE-1 transposition is controlled, particularly at the post-transcriptional level, is incompletely understood. Warkocki et al. now show that 3ʹuridylation of LINE-1 mRNAs by terminal uridyltransferases (TUTases) inhibits LINE-1 retrotransposition.

Credit: Lara Crow/Springer Nature Limited

3ʹUridylation is a prevalent post-transcriptional mRNA modification that in most cases drives mRNA degradation. The authors found that in human cells and mouse testes, LINE-1 mRNAs prominently undergo 3ʹuridylation by two cytoplasmic TUTases, TUT4 and TUT7. Depletion of the TUTases caused an upsurge in LINE-1 retrotransposition. The opposite effect was observed with TUT4 or TUT7 overexpression and the presence of even a single 3ʹuridine considerably reduced the efficiency of retrotransposition. Furthermore, 3ʹuridylation was associated with decreased 3ʹadenylation, and uridylated LINE-1 mRNAs lacking poly(A) tails completely lost the capacity for retrotransposition.

TUT4 (but not TUT7) localized to distinct cytoplasmic foci, where 3ʹuridylation seemed to promote the destabilization of LINE-1 mRNAs. Both TUT4 and TUT7 interacted with a known but insufficiently understood regulator of LINE-1 retrotransposition, the helicase MOV10. In vitro studies revealed competition for LINE-1 mRNAs between MOV10 and the LINE-1-encoded nucleic acid chaperone. This chaperone was shown to inhibit 3ʹuridylaton in a dose-dependent manner, likely by protecting the LINE-1 mRNAs from the activity of TUTases.

The authors propose a model in which, by displacing the protective chaperone from LINE-1 mRNAs, MOV10 promotes TUT4 and TUT7 recruitment and subsequently uridylation at the mRNA 3ʹend. In addition, the presence of 3ʹuridines likely interferes with the initiation of reverse transcription of LINE-1 in the nucleus, which is primed by oligo(dT)–poly(A) interactions.

the presence of 3′uridines likely interferes with the initiation of reverse transcription

Interestingly, another recent study indicates that TUT4 and TUT7 uridylate RNAs of animal RNA viruses, thereby restricting viral replication. This is perhaps not surprising, considering the extensive mechanistic similarity between retrotransposons and retroviruses — RNA viruses that use reverse transcription and integration into host DNA as a part of their lifecycle. Thus, studies of retrotransposon restriction could provide valuable insights into antiviral responses.