title: p53 induces formation of NEAT1 lncRNA-containing paraspeckles that modulate replication stress response and chemosensitivity.
abstract: In a search for mediators of the p53 tumor suppressor pathway, which induces pleiotropic and often antagonistic cellular responses, we identified the long noncoding RNA (lncRNA) NEAT1. NEAT1 is an essential architectural component of paraspeckle nuclear bodies, whose pathophysiological relevance remains unclear. Activation of p53, pharmacologically or by oncogene-induced replication stress, stimulated the formation of paraspeckles in mouse and human cells. Silencing Neat1 expression in mice, which prevents paraspeckle formation, sensitized preneoplastic cells to DNA-damage-induced cell death and impaired skin tumorigenesis. We provide mechanistic evidence that NEAT1 promotes ATR signaling in response to replication stress and is thereby engaged in a negative feedback loop that attenuates oncogene-dependent activation of p53. NEAT1 targeting in established human cancer cell lines induced synthetic lethality with genotoxic chemotherapeutics, including PARP inhibitors, and nongenotoxic activation of p53. This study establishes a key genetic link between NEAT1 paraspeckles, p53 biology and tumorigenesis and identifies NEAT1 as a promising target to enhance sensitivity of cancer cells to both chemotherapy and p53 reactivation therapy.
authors.affiliation: Laboratory for Molecular Cancer Biology, Center for the Biology of Disease, VIB, KU Leuven, Leuven, Belgium.|Laboratory for Molecular Cancer Biology, Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Carmen
authors.initials: C
authors.lastname: Adriaens
authors.affiliation: Laboratory for Molecular Cancer Biology, Center for the Biology of Disease, VIB, KU Leuven, Leuven, Belgium.|Laboratory for Molecular Cancer Biology, Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Laura
authors.initials: L
authors.lastname: Standaert
authors.affiliation: Laboratory for Molecular Cancer Biology, Center for the Biology of Disease, VIB, KU Leuven, Leuven, Belgium.|Laboratory for Molecular Cancer Biology, Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Jasmine
authors.initials: J
authors.lastname: Barra
authors.affiliation: Université Libre de Bruxelles, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Bruxelles, Belgium.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Latil
authors.affiliation: Laboratory of Computational Biology, Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Annelien
authors.initials: A
authors.lastname: Verfaillie
authors.affiliation: Laboratory for Mechanisms of Cell Transformation, Center for the Biology of Disease, VIB, KU Leuven, Leuven, Belgium.|Laboratory for Mechanisms of Cell Transformation, Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Kalev
authors.affiliation: Vesalius Research Center, VIB, KU Leuven, Leuven, Belgium.|Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Bram
authors.initials: B
authors.lastname: Boeckx
authors.affiliation: The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK.
authors.forename: Paul W G
authors.initials: PW
authors.lastname: Wijnhoven
authors.affiliation: Mouse Histopathology Core Facility, Center for the Biology of Disease, VIB, KU Leuven, Leuven, Belgium.
authors.forename: Enrico
authors.initials: E
authors.lastname: Radaelli
authors.affiliation: Section of Pathology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.|Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: William
authors.initials: W
authors.lastname: Vermi
authors.affiliation: Laboratory for Molecular Cancer Biology, Center for the Biology of Disease, VIB, KU Leuven, Leuven, Belgium.|Laboratory for Molecular Cancer Biology, Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Eleonora
authors.identifier: 0000-0002-2898-748X
authors.initials: E
authors.lastname: Leucci
authors.affiliation: Université Libre de Bruxelles, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Bruxelles, Belgium.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Lapouge
authors.affiliation: Université Libre de Bruxelles, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Bruxelles, Belgium.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Beck
authors.affiliation: Laboratory of Translational Cell and Tissue Research, Department of Pathology, KU Leuven and UZ Leuven, Leuven, Belgium.
authors.forename: Joost
authors.initials: J
authors.lastname: van den Oord
authors.affiliation: RNA Biology Laboratory, RIKEN, Wako, Japan.|Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Nakagawa
authors.affiliation: Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Hirose
authors.affiliation: Laboratory for Mechanisms of Cell Transformation, Center for the Biology of Disease, VIB, KU Leuven, Leuven, Belgium.|Laboratory for Mechanisms of Cell Transformation, Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Anna A
authors.initials: AA
authors.lastname: Sablina
authors.affiliation: Vesalius Research Center, VIB, KU Leuven, Leuven, Belgium.|Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.affiliation: Laboratory of Computational Biology, Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Stein
authors.initials: S
authors.lastname: Aerts
authors.affiliation: Université Libre de Bruxelles, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Bruxelles, Belgium.|WELBIO, Université Libre de Bruxelles, Bruxelles, Belgium.
authors.forename: Cédric
authors.initials: C
authors.lastname: Blanpain
authors.affiliation: Laboratory for Molecular Cancer Biology, Center for the Biology of Disease, VIB, KU Leuven, Leuven, Belgium.|Laboratory for Molecular Cancer Biology, Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Marine
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D004249:DNA Damage; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D051379:Mice; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology; D011230:Precancerous Conditions / Q000235:genetics; D016016:Proportional Hazards Models; D062085:RNA, Long Noncoding / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C577276:NEAT1 long non-coding RNA, human; C577275:NEAT1 long non-coding RNA, mouse; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D062085:RNA, Long Noncoding; D016159:Tumor Suppressor Protein p53; C576897:Atr protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins