Tex19.1Restricts LINE-1 Mobilisation in Mouse Embryonic Stem Cells

Abstract

Mobilisation of retrotransposons to new genomic locations is a significant driver of mammalian genome evolution. In humans, retrotransposon mobilisation is mediated primarily by proteins encoded by LINE-1 (L1) retrotransposons, which mobilise in pluripotent cells early in development.Here we show that TEX19.1, which is induced by developmentally programmed DNA hypomethylation, can directly interact with the L1-encoded protein L1-ORF1p, stimulate its polyubiquitylation and degradation, and restrict L1 mobilisation. We also show that TEX19.1 likely acts, at least in part, through promoting the activity of the E3 ubiquitin ligase UBR2 towards L1-ORF1p. Moreover, we show that loss of Tex19.1 increases L1-ORF1p levels and mobilisation of L1 reporters in pluripotent mouse embryonic stem cells implying that Tex19.1 prevents new retrotransposition-mediated mutations from arising in the germline genome. These data show that post-translational regulation of L1 retrotransposons plays a key role in maintaining transgenerational genome stability in the epigenetically dynamic developing mammalian germline.

Meiotic Cells Counteract Programmed Retrotransposon Activation via RNA-Binding Translational Repressor Assemblies

“…Post-transcriptional pathways, such as miRNA, siRNA, and piRNA, target retrotransposon mRNA for degradation (Bao and Yan, 2012;Dechaud et al, 2019;Yang and Wang, 2016) and RNA modification enzymes, such as cytidine deaminases, prevent reverse transcription of the retrotransposon mRNA into cDNA (Orecchini et al, 2018). Posttranslational regulatory mechanisms act in germ cells to target retrotransposon proteins for premature degradation (MacLennan et al, 2017). Beyond the obvious long-term consequences of uncontrolled retrotransposon proliferation, dysregulation of retrotransposon control can cause acute failures in gamete development.…”