Truncated ORF1 proteins can suppress LINE-1 retrotransposition in trans

Abstract

Long interspersed element 1 (L1) is an autonomous non-LTR retroelement that is active in mammalian genomes. Although retrotranspositionally incompetent and functional L1 loci are present in the same genomes, it remains unknown whether nonfunctional L1s have any trans effect on mobilization of active elements. Using bioinformatic analysis, we identified over a thousand of human L1 loci containing at least one stop codon in their ORF1 sequence. RNAseq analysis confirmed that many of these loci are expressed. We demonstrate that introduction of equivalent stop codons in the fulllength human L1 sequence leads to the expression of truncated ORF1 proteins. When supplied in trans some truncated human ORF1 proteins suppress human L1 retrotransposition. This effect requires the Nterminus and coiled-coil domain (C-C) as mutations within the ORF1p C-C domain abolish the suppressive effect of truncated proteins on L1 retrotransposition. We demonstrate that the expression levels and length of truncated ORF1 proteins influence their ability to suppress L1 retrotransposition. Taken together these findings suggest that L1 retrotransposition may be influenced by coexpression of defective L1 loci and that these L1 loci may reduce accumulation of de novo L1 integration events.