TY - JOUR
T1 - Integrator restrains paraspeckles assembly by promoting isoform switching of the lncRNA NEAT1
AU - Barra, Jasmine
AU - Gaidos, Gabriel S.
AU - Blumenthal, Ezra
AU - Beckedorff, Felipe
AU - Tayar, Mina M.
AU - Kirstein, Nina
AU - Karakac, Tobias K.
AU - Jensen, Torben Heick
AU - Impens, Francis
AU - Gevaert, Kris
AU - Leucci, Eleonora
AU - Shiekhattar, Ramin
AU - Marine, Jean Christophe
N1 - Publisher Copyright:
Copyright © 2020 The Authors, some rights reserved.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/7
Y1 - 2020/7
N2 - 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.
AB - 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.
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U2 - 10.1126/sciadv.aaz9072
DO - 10.1126/sciadv.aaz9072
M3 - Article
C2 - 32937468
AN - SCOPUS:85088434976
VL - 6
JO - Science advances
JF - Science advances
SN - 2375-2548
IS - 27
M1 - eaaz9072
ER -