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Nat Genet. 2016 Nov;48(11):1370-1376. doi: 10.1038/ng.3673. Epub 2016 Sep 26.

An inducible long noncoding RNA amplifies DNA damage signaling.

Author information

1
Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, California, USA.
2
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California, USA.
3
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California, USA.
4
Department of Developmental Biology, Stanford University School of Medicine, Stanford, California, USA.
5
Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
6
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
7
Department of Antisense Drug Discovery, Ionis Pharmaceuticals, Carlsbad, California, USA.

Abstract

Long noncoding RNAs (lncRNAs) are prevalent genes with frequently precise regulation but mostly unknown functions. Here we demonstrate that lncRNAs guide the organismal DNA damage response. DNA damage activated transcription of the DINO (Damage Induced Noncoding) lncRNA via p53. DINO was required for p53-dependent gene expression, cell cycle arrest and apoptosis in response to DNA damage, and DINO expression was sufficient to activate damage signaling and cell cycle arrest in the absence of DNA damage. DINO bound to p53 protein and promoted its stabilization, mediating a p53 auto-amplification loop. Dino knockout or promoter inactivation in mice dampened p53 signaling and ameliorated acute radiation syndrome in vivo. Thus, inducible lncRNA can create a feedback loop with its cognate transcription factor to amplify cellular signaling networks.

PMID:
27668660
PMCID:
PMC5083181
DOI:
10.1038/ng.3673
[Indexed for MEDLINE]
Free PMC Article

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