An Apela RNA-Containing Negative Feedback Loop Regulates p53-Mediated Apoptosis in Embryonic Stem Cells

Cell Stem Cell. 2015 Jun 4;16(6):669-83. doi: 10.1016/j.stem.2015.04.002. Epub 2015 Apr 30.


Maintaining genomic integrity is of paramount importance to embryonic stem cells (ESCs), as mutations are readily propagated to daughter cells. ESCs display hypersensitivity to DNA damage-induced apoptosis (DIA) to prevent such propagation, although the molecular mechanisms underlying this apoptotic response are unclear. Here, we report that the regulatory RNA Apela positively regulates p53-mediated DIA. Apela is highly expressed in mouse ESCs and is repressed by p53 activation, and Apela depletion compromises p53-dependent DIA. Although Apela contains a coding region, this coding ability is dispensable for Apela's role in p53-mediated DIA. Instead, Apela functions as a regulatory RNA and interacts with hnRNPL, which prevents the mitochondrial localization and activation of p53. Together, these results describe a tri-element negative feedback loop composed of p53, Apela, and hnRNPL that regulates p53-mediated DIA, and they further demonstrate that regulatory RNAs add a layer of complexity to the apoptotic response of ESCs after DNA damage.

Publication types

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

MeSH terms

  • 3' Untranslated Regions / genetics
  • Amino Acid Sequence
  • Animals
  • Apoptosis* / genetics
  • Base Sequence
  • DNA Damage
  • Enhancer Elements, Genetic / genetics
  • Feedback, Physiological*
  • Genetic Loci
  • Heterogeneous-Nuclear Ribonucleoproteins / chemistry
  • Heterogeneous-Nuclear Ribonucleoproteins / metabolism
  • Mice
  • Mitochondria / metabolism
  • Molecular Sequence Data
  • Mouse Embryonic Stem Cells / cytology*
  • Mouse Embryonic Stem Cells / metabolism*
  • Open Reading Frames / genetics
  • Protein Binding / genetics
  • RNA / metabolism*
  • Tumor Suppressor Protein p53 / metabolism*


  • 3' Untranslated Regions
  • Heterogeneous-Nuclear Ribonucleoproteins
  • Tumor Suppressor Protein p53
  • RNA

Associated data

  • GEO/GSE65491