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Integrator restrains paraspeckles assembly by promoting isoform switching of the lncRNA NEAT1

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  • Jasmine Barra, Flanders Institute for Biotechnology, KU Leuven, Ghent University
  • ,
  • Gabriel S. Gaidos, University of Miami
  • ,
  • Ezra Blumenthal, University of Miami
  • ,
  • Felipe Beckedorff, University of Miami
  • ,
  • Mina M. Tayar, University of Miami
  • ,
  • Nina Kirstein, University of Miami
  • ,
  • Tobias K. Karakac, University of Manitoba
  • ,
  • Torben Heick Jensen
  • Francis Impens, Flanders Institute for Biotechnology, Ghent University, VIB Proteomics Core
  • ,
  • Kris Gevaert, Flanders Institute for Biotechnology, Ghent University
  • ,
  • Eleonora Leucci, KU Leuven
  • ,
  • Ramin Shiekhattar, University of Miami
  • ,
  • Jean Christophe Marine, Flanders Institute for Biotechnology, KU Leuven

RNA 3' end processing provides a source of transcriptome diversification which affects various (patho)-physiological processes. A prime example is the transcript isoform switch that leads to the read-through expression of the long non-coding RNA NEAT1_2, at the expense of the shorter polyadenylated transcript NEAT1_1. NEAT1_2 is required for assembly of paraspeckles (PS), nuclear bodies that protect cancer cells from oncogene-induced replication stress and chemotherapy. Searching for proteins that modulate this event, we identified factors involved in the 3' end processing of polyadenylated RNA and components of the Integrator complex. Perturbation experiments established that, by promoting the cleavage of NEAT1_2, Integrator forces NEAT1_2 to NEAT1_1 isoform switching and, thereby, restrains PS assembly. Consistently, low levels of Integrator subunits correlated with poorer prognosis of cancer patients exposed to chemotherapeutics. Our study establishes that Integrator regulates PS biogenesis and a link between Integrator, cancer biology, and chemosensitivity, which may be exploited therapeutically.

OriginalsprogEngelsk
Artikelnummereaaz9072
TidsskriftScience Advances
Vol/bind6
Nummer27
Antal sider17
ISSN2375-2548
DOI
StatusUdgivet - 2020

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