A TP53 Intron-Derived Peptide Promotes Tumor Survival

During transcription, alternative cleavage and polyadenylation (APA) produces transcripts that differ in their 3 ends without changing DNA sequences. We previously found that leukemia cells leverage intronic APA (IPA) to generate shorter RNA isoforms, which perturbs the expression and function of tumor suppressor genes. Besides protein-coding RNA, we observed that leukemia cells express numerous long non-coding RNAs through IPA, with most of them undocumented and uncharacterized. Here, we report a non-coding IPA isoform in the TP53 gene. With a custom-made antibody, we found that this isoform produces a non-canonical peptide, IDP1 (IPA-Derived Protein 1), using a cryptic open reading frame. The expression was observed in leukemia patients and blood cancer cell lines. Although IDP1 is nested in the TP53 gene, a well-known tumor suppressor, we revealed the oncogenic role of IDP1 in enhancing cell survival during drug treatments, as well as promoting tumor formation in vivo. With proteomic approaches and functional studies, our data suggested that IDP1 increases cell viability by regulating apoptotic signaling, cell cycle, and DNA damage responses. Mechanistically, IDP1 does not abrogate the accumulation and oligomerization of p53 under drug treatments, nor did it interact with p53, indicating that IDP1s impact on survival pathways may not be through influencing p53 protein directly. Collectively, our work highlights that alternative isoforms can be functionally independent of the corresponding genes. In addition to truncating the host genes, IPA can lead to gain of gene products and functions.