An inducible long noncoding RNA amplifies DNA damage signaling

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

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line
  • DNA Damage*
  • Feedback, Physiological
  • Female
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • RNA, Long Noncoding / physiology*
  • Rats
  • Signal Transduction
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • DINO long noncoding RNA, human
  • RNA, Long Noncoding
  • TP53 protein, human
  • Tumor Suppressor Protein p53