The WRAP53α gene undergoes p53 tumor suppressor-dependent transcriptional regulation in response to DNA damage

Abstract

The Wrap53α mRNA transcript regulates expression of the p53 tumor suppressor gene by interacting with the 5-untranslated region of the p53 mRNA transcript. The interaction of p53 mRNA and Wrap53α mRNA, enhances stability of the p53 mRNA and may enhance translation, thus increasing the levels of active p53 protein in the cell. This allows the cell to respond to DNA damage through p53-mediated cell cycle arrest or apoptosis and defects in this pathway lead to tumor formation. In order to determine whether the Wrap53α gene is regulated at the transcriptional level in response to DNA damage, we cloned a region of the Wrap53α gene predicted to carry the promoter and transcriptional regulatory elements of Wrap53 upstream of a reporter gene and tested for alterations in its activity. A transcription factor database search revealed p53 as a potential protein that could bind to numerous sites in the WRAP promoter. Our results indicate that there is a clear transcriptional response to treatment of cells with agents that damage DNA and that p53 protein can bind to at least two of the identified sites in the WRAP promoter. Additional evidence points to the distinct possibility that p53 may be participating in activation of the WRAP gene in response to DNA damage, thus acting as part of a positive feedback loop. Defects in this pathway will disrupt the normal DNA damage response ultimately leading to tumor formation.