1. Introns Protect Eukaryotic Genomes from Transcription-Associated Genetic Instability
- Author
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Vincent Géli, Ana Rita Grosso, Guilhem Janbon, Emeline Coleno, Sérgio F. de Almeida, Amandine Bonnet, Adrien Presle, Sree Rama Chaitanya Sridhara, Abdessamad El-Kaoutari, Benoit Palancade, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Faculdade de Medicina [Lisboa], Universidade de Lisboa = University of Lisbon (ULISBOA), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biologie des ARN des Pathogènes fongiques - RNA Biology of Fungal Pathogens, Institut Pasteur [Paris] (IP), This work was supported by CNRS (to B.P.), Fondation ARC pour la Recherche sur le Cancer (to B.P.), Ligue Nationale contre le Cancer (to B.P., fellowship to A.B. and Equipe Labellisée 2014 to V.G.), EMBO (short-term fellowship to A.B.), Cancéropole PACA (fellowship to A.E.), and Fundaçao para a Ciencia e Tecnologia, Portugal (PTDC/BIM-ONC/0016-2014 to S.F.d.A. and IF/00510/2014 to A.R.G.). Bioinformatic and computing support at CRCM was provided by the CRCM Integrative Bioinformatics and Datacentre IT and Scientific Computing platforms., Universidade de Lisboa (ULISBOA), Institut Pasteur [Paris], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), and Biologie des ARN des Pathogènes fongiques
- Subjects
0301 basic medicine ,Transcription, Genetic ,MESH: Introns ,[SDV]Life Sciences [q-bio] ,Candida glabrata ,mRNA splicing ,MESH: Genotype ,0302 clinical medicine ,MESH: Structure-Activity Relationship ,Minor spliceosome ,Gene Expression Regulation, Fungal ,Databases, Genetic ,DNA, Fungal ,MESH: Candida glabrata ,MESH: Databases, Genetic ,Genetics ,Splice site mutation ,MESH: Genomic Instability ,Nucleic Acid Heteroduplexes ,genetic instability ,MESH: Cryptococcus neoformans ,Group II intron ,R-loops ,MESH: Saccharomyces cerevisiae ,messenger ribonucleoparticle ,Phenotype ,MESH: Nucleic Acid Conformation ,MESH: Schizosaccharomyces ,Ribonucleoproteins ,RNA splicing ,MESH: Fungal Proteins ,transcription ,MESH: Spliceosomes ,MESH: Gene Expression Regulation, Fungal ,MESH: Computational Biology ,Spliceosome ,Genotype ,intron ,RNA Splicing ,Saccharomyces cerevisiae ,Biology ,MESH: Phenotype ,Genomic Instability ,Cell Line ,Fungal Proteins ,Structure-Activity Relationship ,03 medical and health sciences ,mRNP ,MESH: Nucleic Acid Heteroduplexes ,Schizosaccharomyces ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Molecular Biology ,Gene ,MESH: DNA Damage ,MESH: Humans ,MESH: RNA, Fungal ,MESH: Transcription, Genetic ,Intron ,Computational Biology ,RNA ,RNA, Fungal ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,Cell Biology ,Introns ,recombination ,MESH: Cell Line ,MESH: DNA, Fungal ,MESH: Ribonucleoproteins ,030104 developmental biology ,Cryptococcus neoformans ,Spliceosomes ,Nucleic Acid Conformation ,MESH: RNA Splicing ,030217 neurology & neurosurgery ,DNA Damage - Abstract
International audience; Transcription is a source of genetic instability that can notably result from the formation of genotoxic DNA:RNA hybrids, or R-loops, between the nascent mRNA and its template. Here we report an unexpected function for introns in counteracting R-loop accumulation in eukaryotic genomes. Deletion of endogenous introns increases R-loop formation, while insertion of an intron into an intronless gene suppresses R-loop accumulation and its deleterious impact on transcription and recombination in yeast. Recruitment of the spliceosome onto the mRNA, but not splicing per se, is shown to be critical to attenuate R-loop formation and transcription-associated genetic instability. Genome-wide analyses in a number of distant species differing in their intron content, including human, further revealed that intron-containing genes and the intron-richest genomes are best protected against R-loop accumulation and subsequent genetic instability. Our results thereby provide a possible rationale for the conservation of introns throughout the eukaryotic lineage.
- Published
- 2017
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