DNA Damage-Induced RORα Is Crucial for p53 Stabilization and Increased Apoptosis

SummaryA critical component of the DNA damage response is the p53 tumor suppressor, and aberrant p53 function leads to uncontrolled cell proliferation and malignancy. Several molecules have been shown to regulate p53 stability; however, genome-wide systemic approaches for determining the affected, specific downstream target genes have not been extensively studied. Here, we first identified an orphan nuclear receptor, RORα, as a direct target gene of p53, which contains functional p53 response elements. The functional consequences of DNA damage-induced RORα are to stabilize p53 and activate p53 transcription in a HAUSP/Usp7-dependent manner. Interestingly, microarray analysis revealed that RORα-mediated p53 stabilization leads to the activation of a subset of p53 target genes that are specifically involved in apoptosis. We further confirmed that RORα enhances p53-dependent, in vivo apoptotic function in the Drosophila model system. Together, we determined that RORα is a p53 regulator that exerts its role in increased apoptosis via p53.

► Identification of RORα as a p53 target gene induced by DNA damage ► RORα regulates stability and transcription of p53 in a HAUSP-dependent manner ► Genome-wide approaches for determining RORα-dependent p53 target genes ► RORα regulates a subset of p53-responsive genes specifically involved in apoptosis