title: Human regulator of telomere elongation helicase 1 (RTEL1) is required for the nuclear and cytoplasmic trafficking of pre-U2 RNA.
abstract: Hoyeraal-Hreidarsson syndrome (HHS) is a severe form of Dyskeratosis congenita characterized by developmental defects, bone marrow failure and immunodeficiency and has been associated with telomere dysfunction. Recently, mutations in Regulator of Telomere ELongation helicase 1 (RTEL1), a helicase first identified in Mus musculus as being responsible for the maintenance of long telomeres, have been identified in several HHS patients. Here we show that RTEL1 is required for the export and the correct cytoplasmic trafficking of the small nuclear (sn) RNA pre-U2, a component of the major spliceosome complex. RTEL1-HHS cells show abnormal subcellular partitioning of pre-U2, defects in the recycling of ribonucleotide proteins (RNP) in the cytoplasm and splicing defects. While most of these phenotypes can be suppressed by re-expressing the wild-type protein in RTEL1-HHS cells, expression of RTEL1 mutated variants in immortalized cells provokes cytoplasmic mislocalizations of pre-U2 and other RNP components, as well as splicing defects, thus phenocopying RTEL1-HHS cellular defects. Strikingly, expression of a cytoplasmic form of RTEL1 is sufficient to correct RNP mislocalizations both in RTEL1-HHS cells and in cells expressing nuclear mutated forms of RTEL1. This work unravels completely unanticipated roles for RTEL1 in RNP trafficking and strongly suggests that defects in RNP biogenesis pathways contribute to the pathology of HHS.
authors: Telomeres & Cancer laboratory, CNRS, 'Labellisé Ligue', Institut Curie, 26 rue d'Ulm, Paris 75248, France Sorbonne Universités, Paris 06, Paris F-75005, France PSL Research University, Paris, France.
authors: Michael
authors: M
authors: Schertzer
authors: Telomeres & Cancer laboratory, CNRS, 'Labellisé Ligue', Institut Curie, 26 rue d'Ulm, Paris 75248, France Sorbonne Universités, Paris 06, Paris F-75005, France PSL Research University, Paris, France.
authors: Karina
authors: K
authors: Jouravleva
authors: Telomeres & Cancer laboratory, CNRS, 'Labellisé Ligue', Institut Curie, 26 rue d'Ulm, Paris 75248, France Sorbonne Universités, Paris 06, Paris F-75005, France PSL Research University, Paris, France.
authors: Mylene
authors: M
authors: Perderiset
authors: Laboratory of Proteomic Mass Spectrometry, Institut Curie, Paris, France.
authors: Florent
authors: F
authors: Dingli
authors: Laboratory of Proteomic Mass Spectrometry, Institut Curie, Paris, France.
authors: Damarys
authors: D
authors: Loew
authors: INSERM UMR 1163, Laboratory of Genome Dynamics in the Immune System, Paris, France Université Sorbonne Paris Cité, Université Paris Descartes, Institut Imagine, Paris, France.
authors: Tangui
authors: T
authors: Le Guen
authors: IPMC-CNRS UMR7275-Valbonne, France Université de Nice Sophia-Antipolis, Nice 06560, France.
authors: Barbara
authors: B
authors: Bardoni
authors: INSERM UMR 1163, Laboratory of Genome Dynamics in the Immune System, Paris, France Université Sorbonne Paris Cité, Université Paris Descartes, Institut Imagine, Paris, France.
authors: Jean-Pierre
authors: JP
authors: de Villartay
authors: INSERM UMR 1163, Laboratory of Genome Dynamics in the Immune System, Paris, France Université Sorbonne Paris Cité, Université Paris Descartes, Institut Imagine, Paris, France.
authors: Patrick
authors: P
authors: Revy
authors: Telomeres & Cancer laboratory, CNRS, 'Labellisé Ligue', Institut Curie, 26 rue d'Ulm, Paris 75248, France Sorbonne Universités, Paris 06, Paris F-75005, France PSL Research University, Paris, France Arturo.Londono@curie.fr.
authors: Arturo
authors: A
authors: Londoño-Vallejo
mesh_terms: D001483:Base Sequence; D001692:Biological Transport; D015152:Blotting, Northern; D002467:Cell Nucleus / Q000378:metabolism*; D002853:Chromatography, Liquid; D003593:Cytoplasm / Q000378:metabolism*; D004265:DNA Helicases / Q000235:genetics / Q000502:physiology*; D017931:DNA Primers; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D016133:Polymerase Chain Reaction; D012322:RNA Precursors / Q000378:metabolism*; D034741:RNA, Small Interfering; D012342:RNA, Small Nuclear / Q000378:metabolism*; D053719:Tandem Mass Spectrometry
chemical_list: D017931:DNA Primers; D012322:RNA Precursors; D034741:RNA, Small Interfering; D012342:RNA, Small Nuclear; C405484:U2 small nuclear RNA; C532890:RTEL1 protein, human; D004265:DNA Helicases
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