p53 activates the long noncoding RNA Pvt1b to inhibit Myc and suppress tumorigenesis

P53 activation in response to cellular stress has long been known to result in downregulation of c-myc, a gene that is frequently overexpressed in cancer due to its role in promoting cellular proliferation. However, the mechanism underlying this p53 dependent myc repression is poorly understood. Here we report p53 regulation of the lncRNA PVT1, a neighboring myc gene which is upregulated following p53 activation via p53 binding to a canonical p53 response element (p53RE) in the first intron of PVT1. Specifically, we find that p53 activation results in induction of an isoform of PVT1 initiated from an alternative first exon, which we have termed PVT1alt. When the PVT1 p53RE is mutated and PVT1alt induction is inhibited, we observe increased levels of myc mRNA in cells undergoing DNA damage or oncogenic stress and corresponding increases in cellular proliferation. The PVT1alt RNA is required for this p53-dependent myc repression, suggesting a important growth suppressive role for this lncRNA in the p53 response. Our study reveals a novel mode of myc regulation in cis by an alternative lncRNA isoform, providing insight into an important mechanism of crosstalk between the p53 and myc transcriptional networks. RNA seq from WT MEFs infected with a sgRNA targeting the PVT1 p53 response element or a control sgRNA, untreated or treated with doxorubicin for 24 hours. Three biological replicates are included.