Stress out the LINEs

Abstract

Occupying 17% of human genome, the mobile long interspersed element 1 (LINE-1 or L1) continues to modulate the landscape of our genome by inserting into new loci and, as a result, causing sporadic diseases. It is not surprising that human cells have evolved a battery of mechanisms to control and limit the activity of LINE-1. Our recent study unravels such a mechanism that is imposed by the stress granule pathway. This mechanism functions by sequestering the LINE-1 RNA-protein complex within the cytoplasmic stress granules and thus inhibiting the nuclear import of LINE-1 RNA and its subsequent reverse transcription and integration into cellular DNA. Conditions that promote stress granule formation, such as expression of the SAMHD1 protein, further reduce LINE-1 retrotransposition.KEYWORDS host restriction; LINE-1; SAMHD1; stress granule; retrotransposition Approximately 45% of human genome has been derived from transposable elements. 1 These include DNA transposons, long terminal repeat (LTR) retrotransposons (also called endogenous retroviruses), and non-LTR retrotransposons. Long interspersed element 1 (LINE-1) belongs to non-LTR retrotransposons and comprises »17% of human genome. 1 Compared to the other transposons that have mostly become inactive, approximately 100 copies of LINE-1 are still active. 2 Retrotransposition of these LINE-1s is associated with nearly 100 human diseases. 3 LINE-1 encodes two proteins called ORF1 and ORF2. ORF1 is an RNA-binding protein and associates with LINE-1 RNA. [4][5][6][7] ORF2 is an enzyme that has endonuclease and reverse transcriptase activities. 8,9 ORF1, ORF2 and LINE-1 RNA together form an RNP complex that needs to enter the nucleus where LINE-1 RNA is reverse transcribed and integrated into cellular DNA. [10][11][12] Humans have survived LINE-1 invasion and amplification over millions of years thanks to the evolution of a battery of mechanisms that control LINE-1 activity. Some of these mechanisms begin to be unraveled as a result of intensive research in the past couple of decades. One such mechanism is suppression of LINE-1 transcription by methylating LINE-1 DNA. [13][14][15] In support of this mechanism, knockdown or knockout genes that are involved in DNA methylation leads to increase in the activities of LINE-1 and other transposons. 13 In the course of embryonic development there are a couple of waves of DNA demythlyation. DNA demethylation inevitably activates LINE-1 RNA expression. 16 To control retrotransposition of LINE-1 and other transposable elements, primordial germ cells (PGCs) are equipped with the piRNA machinery to inactivate LINE-1 so as to protect the integrity of genome DNA in germ cells. 17,18 Recent studies have revealed that cells have a rich layer of mechanisms that check LINE-1 activity at the post-transcription stage. Many of these mechanisms involve cellular factors that have been shown to restrict viral infections. One example is the APOBEC family of proteins that are cytidine deaminase and inactivate viral or LINE-1 DNA by intro...