Abstract
Mobilization of retrotransposons to new genomic locations is a significant driver of mammalian genome evolution, but these mutagenic events can also cause genetic disorders. In humans, retrotransposon mobilization is mediated primarily by proteins encoded by LINE-1 (L1) retrotransposons, which mobilize 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 mobilization. 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, loss of Tex19.1 increases L1-ORF1p levels and L1 mobilization in pluripotent mouse embryonic stem cells, implying that Tex19.1 prevents de novo retrotransposition in the pluripotent phase of the germline cycle. These data show that post-translational regulation of L1 retrotransposons plays a key role in maintaining trans-generational genome stability in mammals.
Highlights
Retrotransposons are mobile genetic elements that comprise around 40% of mammalian genomes (Beck et al, 2011; Hancks and Kazazian, 2016; Richardson et al, 2014a)
We show that TEX19.1 likely controls L1-ORF1p abundance in concert with UBR2, an E3 ubiquitin ligase that we show physically interacts with and regulates L1-ORF1p levels in vivo
Here we show that Tex19.1 has a role in the post-translational regulation of L1-ORF1p steady-state levels in these cells
Summary
Retrotransposons are mobile genetic elements that comprise around 40% of mammalian genomes (Beck et al, 2011; Hancks and Kazazian, 2016; Richardson et al, 2014a). Retrotransposons are a source of genetic variation that shape genome evolution and mammalian development, but their mobilization can cause mutations associated with a variety of genetic diseases and cancers (Beck et al, 2011; Hancks and Kazazian, 2016; Richardson et al, 2014a; Garcia-Perez et al, 2016).
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