WRAP53 Unwrapped; Roles in Nuclear Architecture and Cancer

Abstract: WRAP53 is a gene of multiple functions; it encodes for a natural antisense transcript that regulates the actions of the tumour suppressor p53, and it gives rise to a protein with oncogenic properties that is important for Cajal body formation and maintenance. Natural antisense transcripts are a group of regulatory RNAs implicated in many aspects of eukaryotic gene expression including transcription, RNA localization, translation and RNA stability. Even though up to 70% of all human genes may overlap in an antisense fashion, little is known about their biological significance. In this work, we have identified a natural antisense transcript of p53 that regulates the steady-state levels of endogenous p53 mRNA and the induction of p53 in response to DNA damage. p53 is a transcription factor that upon DNA damage and other types of cellular stress induces either growth arrest or apoptosis. The significance of p53 in cancer is clearly demonstrated by the fact that approximately 50% of human cancers carry alterations within the p53 gene and that the remaining tumours frequently show other defects within the p53 pathway. Our discovery that WRAP53 stabilizes the p53 mRNA by targeting its 5'untranslated region, reveals a novel pathway for p53 regulation and also suggests a novel therapeutic strategy for cancer treatment. The WRAP53 gene also codes for a protein that has a major role in Cajal body integrity and function. Cajal bodies are nuclear structures implicated in diverse functions such as maturation of the splicing machinery and telomere biogenesis. The WRAP53 protein has been shown to direct small Cajal body-specific RNAs, including the TERT, the RNA part of the telomerase complex, to these nuclear structures. We reveal that WRAP53 in addition directs the survival of motor neuron (SMN) complex to Cajal bodies and that WRAP53 is essential for Cajal body integrity. Our findings further highlight the role of WRAP53 as a Cajal body recruitment factor and contribute to our understanding of the molecular mechanisms behind Cajal body formation. Interestingly, we also find that WRAP53 has oncogenic properties and is overexpressed in human cancers in comparison to primary cells. Moreover, knockdown of WRAP53 leads to massive apoptosis through the intrinsic mitochondrial pathway. Human cancer cells are more sensitive to WRAP53 depletion as compared to normal human fibroblasts, identifying WRAP53 as a novel therapeutic target in cancer. Altogether, our findings suggest an important role of the WRAP53 RNA and protein in tumourigenesis with great implications in cancer therapy.