The tumor suppressor microRNA let-7 inhibits human LINE-1 retrotransposition
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AuthorRubio Roldan, Alejandro; Peris, Guillermo; Sánchez, Laura; Tristán Ramos, Pablo; Amador Cubero, Suyapa; Rodríguez Heras, Sara
Tristán-Ramos, P., Rubio-Roldan, A., Peris, G., Sánchez, L., Amador-Cubero, S., Viollet, S., ... & Heras, S. R. (2020). The tumor suppressor microRNA let-7 inhibits human LINE-1 retrotransposition. Nature communications, 11(1), 1-14. [doi:10.1038/s41467-020-19430-4]
SponsorshipEuropean Research Council (ERC) ERC-2009-StG 243312; French National Research Agency (ANR) ANR-11-LABX-0028-01 ANR-15-IDEX-01; Centre National de la Recherche Scientifique (CNRS) 3546; University Hospital Federation (FHU) OncoAge; MINECO PEJ-2014-A-31985 SAF2015-71589-P; MINECO by European Regional Development Fund SAF2015-71589-P; Spanish Government RYC-2016-21395; Career Integration Grant-Marie Curie FP7-PEOPLE-2011-CIG-303812
Nearly half of the human genome is made of transposable elements (TEs) whose activity continues to impact its structure and function. Among them, Long INterspersed Element class 1 (LINE-1 or L1) elements are the only autonomously active TEs in humans. L1s are expressed and mobilized in different cancers, generating mutagenic insertions that could affect tumor malignancy. Tumor suppressor microRNAs are ∼22nt RNAs that post-transcriptionally regulate oncogene expression and are frequently downregulated in cancer. Here we explore whether they also influence L1 mobilization. We show that downregulation of let-7 correlates with accumulation of L1 insertions in human lung cancer. Furthermore, we demonstrate that let-7 binds to the L1 mRNA and impairs the translation of the second L1-encoded protein, ORF2p, reducing its mobilization. Overall, our data reveals that let-7, one of the most relevant microRNAs, maintains somatic genome integrity by restricting L1 retrotransposition.