An Apela RNA-Containing Negative Feedback Loop Regulates p53-Mediated Apoptosis in Embryonic Stem Cells.
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.
Cancer and Stem Cell Epigenetics, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Mangmang
M
Li
Cancer and Stem Cell Epigenetics, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Hongfeng
H
Gou
Signaling and Oncogenesis Section, Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Brajendra K
BK
Tripathi
Howard Hughes Medical Institute, Department of Biological Chemistry, University of Michigan, 1150 West Medical Center Drive MSRB3, 3315, Ann Arbor, MI 48109, USA.
Jing
J
Huang
Cancer and Stem Cell Epigenetics, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Shunlin
S
Jiang
Cancer and Stem Cell Epigenetics, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Wendy
W
Dubois
Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, P.O. Box B, Frederick, MD 21702, USA.
Tim
T
Waybright
Howard Hughes Medical Institute, Department of Biological Chemistry, University of Michigan, 1150 West Medical Center Drive MSRB3, 3315, Ann Arbor, MI 48109, USA.
Ming
M
Lei
Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Executive Plaza South, Room 8040, Bethesda, MD 20892, USA.
Jianxin
J
Shi
Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, P.O. Box B, Frederick, MD 21702, USA.
Ming
M
Zhou
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.
Jing
J
Huang
D020413:3' Untranslated Regions / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D004249:DNA Damage; D004742:Enhancer Elements, Genetic / Q000235:genetics; D025461:Feedback, Physiological; D056426:Genetic Loci; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D008969:Molecular Sequence Data; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D016366:Open Reading Frames / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D012313:RNA / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D020413:3' Untranslated Regions; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D016159:Tumor Suppressor Protein p53; D012313:RNA