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Nat Med. 2016 Aug;22(8):861-8. doi: 10.1038/nm.4135. Epub 2016 Jul 4.

p53 induces formation of NEAT1 lncRNA-containing paraspeckles that modulate replication stress response and chemosensitivity.

Author information

1
Laboratory for Molecular Cancer Biology, Center for the Biology of Disease, VIB, KU Leuven, Leuven, Belgium.
2
Laboratory for Molecular Cancer Biology, Center for Human Genetics, KU Leuven, Leuven, Belgium.
3
Université Libre de Bruxelles, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Bruxelles, Belgium.
4
Laboratory of Computational Biology, Center for Human Genetics, KU Leuven, Leuven, Belgium.
5
Laboratory for Mechanisms of Cell Transformation, Center for the Biology of Disease, VIB, KU Leuven, Leuven, Belgium.
6
Laboratory for Mechanisms of Cell Transformation, Center for Human Genetics, KU Leuven, Leuven, Belgium.
7
Vesalius Research Center, VIB, KU Leuven, Leuven, Belgium.
8
Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium.
9
The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK.
10
Mouse Histopathology Core Facility, Center for the Biology of Disease, VIB, KU Leuven, Leuven, Belgium.
11
Section of Pathology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
12
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
13
Laboratory of Translational Cell and Tissue Research, Department of Pathology, KU Leuven and UZ Leuven, Leuven, Belgium.
14
RNA Biology Laboratory, RIKEN, Wako, Japan.
15
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
16
Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
17
WELBIO, Université Libre de Bruxelles, Bruxelles, Belgium.

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.

PMID:
27376578
DOI:
10.1038/nm.4135
[Indexed for MEDLINE]

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