title: A recently evolved class of alternative 3'-terminal exons involved in cell cycle regulation by topoisomerase inhibitors.
abstract: Alternative 3'-terminal exons, which use intronic polyadenylation sites, are generally less conserved and expressed at lower levels than the last exon of genes. Here we discover a class of human genes, in which the last exon appeared recently during evolution, and the major gene product uses an alternative 3'-terminal exon corresponding to the ancestral last exon of the gene. This novel class of alternative 3'-terminal exons are downregulated on a large scale by doxorubicin, a cytostatic drug targeting topoisomerase II, and play a role in cell cycle regulation, including centromere-kinetochore assembly. The RNA-binding protein HuR/ELAVL1 is a major regulator of this specific set of alternative 3'-terminal exons. HuR binding to the alternative 3'-terminal exon in the pre-messenger RNA promotes its splicing, and is reduced by topoisomerase inhibitors. These findings provide new insights into the evolution, function and molecular regulation of alternative 3'-terminal exons.
authors.affiliation: 1] INSERM U1052, 28 rue Laennec, Lyon F-69000, France [2] CNRS UMR5286, 28 rue Laennec, Lyon F-69000, France [3] Centre Léon Bérard, 28 rue Laennec, Lyon F-69000, France [4] Centre de Recherche en Cancérologie de Lyon, 28 rue Laennec, Lyon F-69000, France [5] Université de Lyon, Lyon 69007, France [6].
authors.forename: Martin
authors.initials: M
authors.lastname: Dutertre
authors.affiliation: 1] INSERM U1052, 28 rue Laennec, Lyon F-69000, France [2] CNRS UMR5286, 28 rue Laennec, Lyon F-69000, France [3] Centre Léon Bérard, 28 rue Laennec, Lyon F-69000, France [4] Centre de Recherche en Cancérologie de Lyon, 28 rue Laennec, Lyon F-69000, France [5] Université de Lyon, Lyon 69007, France [6].
authors.forename: Fatima Zahra
authors.initials: FZ
authors.lastname: Chakrama
authors.affiliation: 1] INSERM U1052, 28 rue Laennec, Lyon F-69000, France [2] CNRS UMR5286, 28 rue Laennec, Lyon F-69000, France [3] Centre Léon Bérard, 28 rue Laennec, Lyon F-69000, France [4] Centre de Recherche en Cancérologie de Lyon, 28 rue Laennec, Lyon F-69000, France [5] Université de Lyon, Lyon 69007, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Combe
authors.affiliation: 1] INSERM U1052, 28 rue Laennec, Lyon F-69000, France [2] CNRS UMR5286, 28 rue Laennec, Lyon F-69000, France [3] Centre Léon Bérard, 28 rue Laennec, Lyon F-69000, France [4] Centre de Recherche en Cancérologie de Lyon, 28 rue Laennec, Lyon F-69000, France [5] Université de Lyon, Lyon 69007, France.
authors.forename: François-Olivier
authors.initials: FO
authors.lastname: Desmet
authors.affiliation: 1] INSERM U1052, 28 rue Laennec, Lyon F-69000, France [2] CNRS UMR5286, 28 rue Laennec, Lyon F-69000, France [3] Centre Léon Bérard, 28 rue Laennec, Lyon F-69000, France [4] Centre de Recherche en Cancérologie de Lyon, 28 rue Laennec, Lyon F-69000, France [5] Université de Lyon, Lyon 69007, France.
authors.forename: Hussein
authors.initials: H
authors.lastname: Mortada
authors.affiliation: 1] INSERM U1052, 28 rue Laennec, Lyon F-69000, France [2] CNRS UMR5286, 28 rue Laennec, Lyon F-69000, France [3] Centre Léon Bérard, 28 rue Laennec, Lyon F-69000, France [4] Centre de Recherche en Cancérologie de Lyon, 28 rue Laennec, Lyon F-69000, France [5] Université de Lyon, Lyon 69007, France.
authors.forename: Micaela
authors.initials: M
authors.lastname: Polay Espinoza
authors.affiliation: 1] INSERM U1052, 28 rue Laennec, Lyon F-69000, France [2] CNRS UMR5286, 28 rue Laennec, Lyon F-69000, France [3] Centre Léon Bérard, 28 rue Laennec, Lyon F-69000, France [4] Centre de Recherche en Cancérologie de Lyon, 28 rue Laennec, Lyon F-69000, France [5] Université de Lyon, Lyon 69007, France.
authors.forename: Lise
authors.initials: L
authors.lastname: Gratadou
authors.affiliation: 1] INSERM U1052, 28 rue Laennec, Lyon F-69000, France [2] CNRS UMR5286, 28 rue Laennec, Lyon F-69000, France [3] Centre Léon Bérard, 28 rue Laennec, Lyon F-69000, France [4] Centre de Recherche en Cancérologie de Lyon, 28 rue Laennec, Lyon F-69000, France [5] Université de Lyon, Lyon 69007, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Auboeuf
mesh_terms: D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002503:Centromere / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D004317:Doxorubicin / Q000494:pharmacology; D000067780:ELAV-Like Protein 1 / Q000235:genetics; D005091:Exons / Q000235:genetics*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D018386:Kinetochores / Q000378:metabolism; D061986:MCF-7 Cells; D059003:Topoisomerase Inhibitors / Q000494:pharmacology*
chemical_list: D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D059003:Topoisomerase Inhibitors; D004317:Doxorubicin