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: Michael Schertzer, Karina Jouravleva, Mylene Perderiset, Florent Dingli, Damarys Loew, Tangui Le Guen, Barbara Bardoni, Jean-Pierre de Villartay, Patrick Revy, Arturo Londoño-Vallejo
• Journal: Nucleic acids research (Nucleic Acids Res) Vol. 43 Issue 3 Pg. 1834-47 (Feb 18 2015) ISSN: 1362-4962 [Electronic] England
• PMID: 25628358 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Chemical References

• DNA Primers
• RNA Precursors
• RNA, Small Interfering
• RNA, Small Nuclear
• U2 small nuclear RNA
• RTEL1 protein, human
• DNA Helicases

Topics

• Base Sequence
• Biological Transport
• Blotting, Northern
• Cell Nucleus (metabolism)
• Chromatography, Liquid
• Cytoplasm (metabolism)
• DNA Helicases (genetics, physiology)
• DNA Primers
• HEK293 Cells
• HeLa Cells
• Humans
• Polymerase Chain Reaction
• RNA Precursors (metabolism)
• RNA, Small Interfering
• RNA, Small Nuclear (metabolism)
• Tandem Mass Spectrometry