Orphan Receptor TR3 Enhances p53 Transactivation and Represses DNA Double-Strand Break Repair in Hepatoma Cells under Ionizing Radiation

Abstract

In response to ionizing radiation (IR)-induced DNA double-strand breaks (DSB), cells elicit an evolutionarily conserved checkpoint response that induces cell cycle arrest and either DNA repair or apoptosis, thereby maintaining genomic stability. DNA-dependent protein kinase (DNA-PK) is a central enzyme involved in DSB repair for mammalian cells that comprises a DNA-PK catalytic subunit and the Ku protein, which act as regulatory elements. DNA-PK also functions as a signaling molecule to selectively regulate p53-dependent apoptosis in response to IR. Herein, we demonstrate that the orphan nuclear receptor TR3 suppresses DSB repair by blocking Ku80 DNA-end binding activity and promoting DNA-PK-induced p53 activity in hepatoma cells. We find that TR3 interacts with Ku80 and inhibits its binding to DNA ends, which then suppresses DSB repair. Furthermore, TR3 is a phosphorylation substrate for DNA-PK and interacts with DNA-PK catalytic subunit in a Ku80-independent manner. Phosphorylated TR3, in turn, enhances DNA-PK-induced phosphorylation and p53 transcription activity, thereby enhancing IR-induced apoptosis in hepatoma cells. Together, our findings reveal novel functions for TR3, not only in DSB repair regulation but also in IR-induced hepatoma cell apoptosis, and they suggest that TR3 is a potential target for cancer radiotherapy.

The NR4A nuclear receptors as potential targets for anti-aging interventions

“…Since NR4A receptors is induced by nutrients [22,83,84] and improve mitochondrial function [30,32], we also expected that these receptors should mediate mitohormesis, an adaptative response to mitochondrial stress that promotes longevity [85,86]. However one study reported that NR4A1 represses DNA repair in hepatoma cells under ionizing irradiation [87]. NR4A1 is also involved in fatty acid cytotoxic activity in b islets pancreatic cells [88].…”

Molecular Pathways: The Role of NR4A Orphan Nuclear Receptors in Cancer

“…These studies suggest a pro-cell-survival role for NR4As by regulating DNA repair. Conversely, a role for NR4A1 in inhibition of DNA repair has been described in hepatocellular carcinoma cell lines (20).…”

“…The DNA repair effect of NR4A receptors may contribute to resistance to radiotherapy or chemotherapy (e.g., bleomycin; refs. 18,20). Manipulation of NR4A/DSB binding may be a strategy to increase tumor sensitivity to chemoradiotherapy.…”

NR4A1 retards adipocyte differentiation or maturation via enhancing GATA2 and p53 expression

“…While knockout NR4A1 resulted in reduced p53 expression, therefore, NR4A1 might indirectly modulate the expression of SREBP‐1c via p53, then hinder excess fat accumulation in adipocytes 18, 19. It has been reported that NR4A1 could either enhance DNA‐dependent protein kinase to increase p53 transcription activity 36 or to cause mouse 3T3 cell double minute 2 (MDM2) to separation from p53, thus to protect p53 from MDM2‐mediated ubiquitination and degradation 37. Herein we confirmed the presence of p53 in adipose tissue and found that p53 expression was reduced in adipose tissues of KO mice compared to WT.…”