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

Autor:	Barra J; Laboratory for Molecular Cancer Biology, Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory for Molecular Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium.; VIB Center for Medical Biotechnology, VIB, 9000 Ghent, Belgium.; Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium.; Laboratory for RNA Cancer Biology, Department of Oncology, LKI, KU Leuven, Leuven, Belgium., Gaidosh GS; Sylvester Comprehensive Cancer Center, Department of Human Genetics, University of Miami Miller School of Medicine, 1501 NW 10th Avenue, Miami, FL 33136, USA., Blumenthal E; Sylvester Comprehensive Cancer Center, Department of Human Genetics, University of Miami Miller School of Medicine, 1501 NW 10th Avenue, Miami, FL 33136, USA., Beckedorff F; Sylvester Comprehensive Cancer Center, Department of Human Genetics, University of Miami Miller School of Medicine, 1501 NW 10th Avenue, Miami, FL 33136, USA., Tayari MM; Sylvester Comprehensive Cancer Center, Department of Human Genetics, University of Miami Miller School of Medicine, 1501 NW 10th Avenue, Miami, FL 33136, USA., Kirstein N; Sylvester Comprehensive Cancer Center, Department of Human Genetics, University of Miami Miller School of Medicine, 1501 NW 10th Avenue, Miami, FL 33136, USA., Karakach TK; Bioinformatics Core Laboratory, Children's Hospital Research Institute of Manitoba (CHRIM), Winnipeg, Manitoba, Canada.; Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada., Jensen TH; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark., Impens F; VIB Center for Medical Biotechnology, VIB, 9000 Ghent, Belgium.; Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium.; VIB Proteomics Core, 9000 Ghent, Belgium., Gevaert K; VIB Center for Medical Biotechnology, VIB, 9000 Ghent, Belgium.; Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium., Leucci E; Laboratory for RNA Cancer Biology, Department of Oncology, LKI, KU Leuven, Leuven, Belgium., Shiekhattar R; Sylvester Comprehensive Cancer Center, Department of Human Genetics, University of Miami Miller School of Medicine, 1501 NW 10th Avenue, Miami, FL 33136, USA., Marine JC; Laboratory for Molecular Cancer Biology, Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory for Molecular Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium.
Jazyk:	angličtina
Zdroj:	Science advances [Sci Adv] 2020 Jul 03; Vol. 6 (27), pp. eaaz9072. Date of Electronic Publication: 2020 Jul 03 (Print Publication: 2020).
DOI:	10.1126/sciadv.aaz9072
Abstrakt:	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. (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu