A TP53 Intron-Derived Peptide Promotes Tumor Survival

Abstract

During transcription, alternative cleavage and polyadenylation (APA) of transcripts produces mRNAs that differ in their 3 ends. We previously found that leukemia cells cleave and polyadenylate transcripts within introns (intronic APA, IPA) to generate truncated RNA isoforms, which perturb the expression and function of corresponding genes. In addition to protein-coding RNA, we found that leukemia cells express numerous putative long non-coding RNAs generated by IPA, with most uncharacterized. Here, we identify an IPA isoform encoded within intron 1 of the TP53 tumor suppressor gene that is translated into a non-canonical protein termed IPADP1 (IPA-derived protein 1). IPADP1 expression was detected in patient leukemia cells and human blood cancer cell lines. We uncovered an oncogenic role for IPADP1 in enhancing cancer cell survival during drug treatments, as well as promoting tumor formation in vivo. Using proteomic and functional studies, our data suggest that IPADP1 increases cell viability by regulating apoptotic signaling, cell cycle, and DNA damage responses. Furthermore, we observed that the expression of p53-IPA is significantly associated with SF3B1 mutations in leukemia patients, suggesting mechanisms for the genesis of this isoform. Our study demonstrates that an IPA isoform could have a function different from its host gene.