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.
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We thank O. Van Goethem, G. Bervoets and S. Peeters for excellent technical assistance; E. Bonomi and M. Bugatti (Fondazione Beretta) for ISH analysis of human cancer samples; and S. Jackson for helpful comments on the manuscript and for imaging facility access. Imaging was done on a Nikon A1 confocal microscope acquired through a Hercules grant type 1 (AKUL/09/037) to W. Annaert. This work was supported by Interuniversitaire Attractiepolen (IUAP), an Institute for Science, Innovation and Technology (IWT) scholarship to C.A. and a Fund for Scientific Research Flanders (FWO) scholarship to L.S. W.V. is supported by Associazione Italiana per la Ricerca sul Cancro (AIRC, IG 15378) and by Ministero Salute (RF-2010-2315888).
The authors declare no competing financial interests.
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Adriaens, C., Standaert, L., Barra, J. et al. p53 induces formation of NEAT1 lncRNA-containing paraspeckles that modulate replication stress response and chemosensitivity. Nat Med 22, 861–868 (2016) doi:10.1038/nm.4135
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