1. The tumor suppressor microRNA let-7 inhibits human LINE-1 retrotransposition
- Author
-
Suyapa Amador-Cubero, Sebastien Viollet, Laura Sánchez, Alejandro Rubio-Roldan, Pablo Tristan-Ramos, Sara R. Heras, Gaël Cristofari, Guillermo Peris, [Tristán-Ramos,P, Rubio-Roldan,A, Peris,G, Sánchez,L, Amador-Cubero,S, Heras,SR] GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government. PTS Granada, Granada, Spain. [Tristán-Ramos,P, Heras,SR] Dept. Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Granada, Spain. [Peris,G] Dept. of Computer Languages and Systems, Universitat Jaume I, Castellón de la Plana, Spain. [Viollet,S, Cristofari,G] Université Côte d’Azur, CNRS, INSERM, IRCAN, Nice, France., The work in the lab of G.C. was supported by the European Research Council (ERC-2009-StG 243312, Retrogenomics), by the French Government (National Research Agency, ANR) through the 'Investments for the Future' programs LABEX SIGNALIFE ANR-11-LABX-0028-01 and IDEX UCAJedi ANR-15-IDEX-01, by CNRS (GDR 3546), and by the University Hospital Federation (FHU) OncoAge.This article is part of the doctoral thesis of P.T.-R., a graduate student in the PhD programme of Biomedicine at the University of Granada, who was supported by MINECO (PEJ-2014-A-31985 and SAF2015-71589-P). S.R.H. is funded by MINECO cofounding by European Regional Development Fund (SAF2015-71589-P), Ramón y Cajal (RYC-2016-21395) and a Career Integration Grant-Marie Curie (FP7-PEOPLE-2011-CIG-303812)., Universidad de Granada = University of Granada (UGR), Centre for Genomics and Oncological Reearch (GENYO), Universitat Jaume I, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Université Côte d'Azur (UCA), ANR-11-LABX-0028,SIGNALIFE,Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie(2011), ANR-15-IDEX-0001,UCA JEDI,Idex UCA JEDI(2015), European Project, European Project: 303812,EC:FP7:PEOPLE,FP7-PEOPLE-2011-CIG,L1-DIGEORGESYNDROME(2012), Cristofari, Gael, Centres d'excellences - Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie - - SIGNALIFE2011 - ANR-11-LABX-0028 - LABX - VALID, Idex UCA JEDI - - UCA JEDI2015 - ANR-15-IDEX-0001 - IDEX - VALID, ERC number 243312, Retrogenomics - INCOMING, Role of LINE-1 retrotransposons in the human disease DiGeorge Syndrome - L1-DIGEORGESYNDROME - - EC:FP7:PEOPLE2012-06-01 - 2016-11-21 - 303812 - VALID, University of Granada [Granada], and Université Nice Sophia Antipolis (... - 2019) (UNS)
- Subjects
0301 basic medicine ,Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Nucleotidyltransferases::DNA Nucleotidyltransferases::DNA-Directed DNA Polymerase::RNA-Directed DNA Polymerase [Medical Subject Headings] ,Lung Neoplasms ,Somatic cell ,General Physics and Astronomy ,Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Esterases::Endonucleases [Medical Subject Headings] ,Retrotransposon ,[SDV.GEN] Life Sciences [q-bio]/Genetics ,Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::RNA::RNA, Untranslated::RNA, Small Untranslated::MicroRNAs [Medical Subject Headings] ,Non-coding RNAs ,law.invention ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] ,0302 clinical medicine ,Lung neoplasms ,law ,Tumor Cells, Cultured ,Transposition ,Genes, Tumor Suppressor ,Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::RNA::RNA, Untranslated::Untranslated Regions::3' Untranslated Regions [Medical Subject Headings] ,Carcinoma de células escamosas ,lcsh:Science ,3' Untranslated Regions ,Cancer genetics ,MicroARNs ,0303 health sciences ,Multidisciplinary ,RNA-Directed DNA Polymerase ,Anatomy::Cells::Cells, Cultured::Tumor Cells, Cultured [Medical Subject Headings] ,Translation (biology) ,3. Good health ,Cell biology ,Gene Expression Regulation, Neoplastic ,030220 oncology & carcinogenesis ,Carcinoma, Squamous Cell ,Transposable element ,Neoplasias pulmonares ,Science ,Carcinoma, squamous cell ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Adenocarcinoma of Lung ,Biology ,Diseases::Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms [Medical Subject Headings] ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression::Protein Biosynthesis [Medical Subject Headings] ,Diseases::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Glandular and Epithelial::Carcinoma::Carcinoma, Squamous Cell [Medical Subject Headings] ,microRNA ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,RNA, Messenger ,Genes Supresores de Tumor ,030304 developmental biology ,Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Genes, Recessive::Genes, Tumor Suppressor [Medical Subject Headings] ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Binding Sites ,Whole Genome Sequencing ,Oncogene ,Genes, tumor suppressor ,General Chemistry ,Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Molecular Structure::Binding Sites [Medical Subject Headings] ,Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::RNA::RNA, Messenger [Medical Subject Headings] ,Endonucleases ,Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Gene Expression Regulation, Neoplastic [Medical Subject Headings] ,Long interspersed nuclear element ,MicroRNAs ,030104 developmental biology ,Long Interspersed Nucleotide Elements ,Phenomena and Processes::Genetic Phenomena::Genetic Structures::Base Sequence::Repetitive Sequences, Nucleic Acid::Interspersed Repetitive Sequences::Retroelements::Long Interspersed Nucleotide Elements [Medical Subject Headings] ,Protein Biosynthesis ,Suppressor ,lcsh:Q ,Human genome - 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., European 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
- Published
- 2020