DNA Damage Induces the lncRNA DINO to Stabilize p53

In response to DNA damage, p53 activates target genes to promote cell-cycle arrest or apoptosis. This signaling cascade can be regulated by control of p53 abundance or p53 stabilization. p53 has been shown to bind to noncoding RNAs, but their role in p53 regulation remains unclear. Schmitt, Garcia, Hung, and colleagues identified a highly conserved DNA damage–induced long noncoding RNA (lncRNA), ultimately named damage induced noncoding (DINO), that is induced by p53 in response to DNA damage, located next to a p53 binding site, and upstream of and transcribed divergently from CDKN1A. DINO depletion prevented the upregulation of a number of p53-responsive genes in response to DNA damage, a majority of which had canonical p53 binding sites, and loss of DINO reduced p53 occupancy at its target genes. Further, DINO was required for DNA damage–induced cell-cycle arrest, and depletion of p53 or DINO had similar effects in allowing cells to continue to divide following DNA damage, altogether indicating that DINO is involved in regulating the p53-dependent DNA damage response. Consistent with these findings, DINO bound to p53 following DNA damage and stabilized p53 to promote expression of p53 target genes. In vivo, Dino deletion resulted in reduced sensitivity to radiation, and mouse embryonic fibroblasts lacking Dino displayed reduced expression of p53 target genes and reduced cell-cycle arrest following DNA damage independent of CDKN1A signaling. The identification of DINO as a DNA damage–induced lncRNA responsible for stabilizing p53 and promoting the p53-dependent DNA damage response reveals an effector mechanism by which lncRNAs can amplify DNA damage signaling and potentially other p53-dependent signaling networks.

Schmitt AM, Garcia JT, Hung T, Flynn RA, Shen Y, Qu K, et al. An inducible long noncoding RNA amplifies DNA damage signaling. Nat Genet 2016 Sep 26 [Epub ahead of print].