The tumor suppressor microRNA let-7 inhibits human LINE-1 retrotransposition

Abstract

19Nearly half of the human genome is made of transposable elements (TEs) 20 whose activity continues to impact its structure and function. Among them, 21 Long INterspersed Element class 1 (LINE-1 or L1) elements are the only 22 autonomously active TEs in humans. L1s are expressed and mobilized in 23 different cancers, generating mutagenic insertions that could affect 24 malignancy. Tumor suppressor microRNAs are 22nt RNAs that post-25 transcriptionally regulate oncogene expression and are frequently 26 downregulated in cancer. Here we explore whether they also influence L1 27 mobilization. We found that downregulation of let-7 correlates with 28 accumulation of L1 insertions in human lung cancer. Furthermore, we 29 demonstrate that let-7 binds to the L1 mRNA and impairs the translation of the 30 second L1-encoded protein, ORF2p, reducing its mobilization. Overall, our 31 data uncover a new role for let-7, one of the most relevant microRNAs, which 32 is to maintain somatic genome integrity by restricting L1 retrotransposition. 33 34 35 Transposable elements (TEs) account for nearly half of the human genome 1 . 36 However, the only TE that remains autonomously active nowadays is a non-37 Long Terminal Repeat (LTR) retrotransposon known as Long INterspersed 38 Element class 1 (LINE-1 or L1), whose mobilization continues to impact our 39 genome 2 . LINE-1s comprise >20% of our DNA 3 but only about 80-100 of the 40 ~500,000 L1 copies present in the average human genome are full-length 41 elements that retain the ability to mobilize and are thus called 42 Retrotransposition-Competent L1s (RC-L1s) 4 . RC-L1s belong to the human-43 2 specific L1Hs subfamily, are 6kb long and encode two proteins (L1-ORF1p and 44 L1-ORF2p) that are indispensable for retrotransposition 5 . However, ORF2p is 45 expressed at a significantly lower level than ORF1p 6,7 , and these differences are 46 thought to be controlled at the level of translation 8 . L1-ORF1p is a 40kDa RNA 47 binding protein with nucleic acid chaperone activity 9,10 , whereas L1-ORF2p is a 48 150 kDa protein with Endonuclease (EN) and Reverse Transcriptase (RT) 49 activities 11,12 . RC--and-ism, involving 50 reverse transcription of an RNA intermediate and insertion of its cDNA copy at 51 a new site in the genome (reviewed in 2 ). Briefly, retrotransposition starts with 52 the transcription of a full-length RC-L1 bicistronic mRNA, which is exported to 53 the cytoplasm and translated, giving rise to L1-ORF1p and L1-ORF2p that bind 54 preferentially to the same L1 mRNA to form a ribonucleoparticle (RNP) 13 . The 55 RNP gains access to the nucleus where retrotransposition occurs by a 56 mechanism known as Target Primed Reverse Transcription (TPRT) 14,15 . During 57 TPRT, the endonuclease activity of L1-ORF2p nicks the genomic DNA, and its 58 reverse transcriptase activity uses the L1 mRNA as a template to generate a new 59 copy of the element in a different genomic location. L1 can target all regions of 60 the genome, but integration is locally dictated by the presence of...

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