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

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

Author information

1
Cancer and Stem Cell Epigenetics, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
2
Signaling and Oncogenesis Section, Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
3
Howard Hughes Medical Institute, Department of Biological Chemistry, University of Michigan, 1150 West Medical Center Drive MSRB3, 3315, Ann Arbor, MI 48109, USA.
4
Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, P.O. Box B, Frederick, MD 21702, USA.
5
Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Executive Plaza South, Room 8040, Bethesda, MD 20892, USA.
6
Cancer and Stem Cell Epigenetics, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. Electronic address: huangj3@mail.nih.gov.

Abstract

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.

PMID:
25936916
PMCID:
PMC4458197
DOI:
10.1016/j.stem.2015.04.002
[Indexed for MEDLINE]
Free PMC Article

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