Activation of Pvt1b isoform contributes to local Pvt1 abundance to repress Myc during stress

Abstract

Many long noncoding RNA (lncRNA) loci harbor multiple alternative isoforms. It is not known whether isoform-specific sequence elements enable distinct functions. Previous work identified two alternative transcription start site (TSS) isoforms in the Pvt1 lncRNA locus - the constitutively expressed Pvt1a and the stress-induced Pvt1b. While the function of Pvt1a is not known, the p53-regulated Pvt1b was shown to act locally to repress the transcription of the neighboring Myc proto-oncogene in response to genotoxic and oncogenic stress. Here, we investigated whether Pvt1b contains isoform-specific repressive sequence elements. Our results revealed that Pvt1b contributes to but is not required for Myc repression. Using in vivo and in vitro models of genotoxic and oncogenic stress, we observed that Pvt1a compensates for Pvt1b loss, resulting in Pvt1b deficiency having a moderate effect on Myc regulation, stress response, and tumor suppression. Long-read sequencing exposed a diversity of stress-induced Pvt1a and Pvt1b isoforms, further arguing against a specialized role for Pvt1b. We propose that p53-induced increase in total Pvt1 abundance, and not isoform-specific activation, represses Myc during stress.