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

Jasmine Barra, Gabriel S. Gaidos, Ezra Blumenthal, Felipe Beckedorff, Mina M. Tayar, Nina Kirstein, Tobias K. Karakac, Torben Heick Jensen, Francis Impens, Kris Gevaert, Eleonora Leucci, Ramin Shiekhattar, Jean Christophe Marine

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbereaaz9072
JournalScience Advances
Volume6
Issue number27
DOIs
StatePublished - Jul 2020

ASJC Scopus subject areas

  • General

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