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

Pablo Tristán-Ramos, Alejandro Rubio-Roldan, Guillermo Peris, Laura Sánchez, Suyapa Amador-Cubero, Sebastien Viollet, Gael Cristofari and Sara R. Heras ()
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Pablo Tristán-Ramos: GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government. PTS Granada
Alejandro Rubio-Roldan: GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government. PTS Granada
Guillermo Peris: GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government. PTS Granada
Laura Sánchez: GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government. PTS Granada
Suyapa Amador-Cubero: GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government. PTS Granada
Sebastien Viollet: Université Côte d’Azur, CNRS, INSERM, IRCAN
Gael Cristofari: Université Côte d’Azur, CNRS, INSERM, IRCAN
Sara R. Heras: GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government. PTS Granada

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-19430-4

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