Abstract
Dysregulated expression of tumor suppressor genes can impair their functions, even promoting oncogenesis. Expression of p53β mRNA can be regulated by alternative splicing and RNA surveillance, otherwise translated to a C-terminal truncated p53 protein with a unique neoepitope. Here, we identified that p53 introns bear the binding sites for serine and arginine-rich splicing factor 3 (SRSF3). SRSF3 binding to p53 intron 9 facilitates upstream frameshift 1 (UPF1) recruitment and regulates production of p53β mRNA. We also demonstrated that this ternary ribonucleoprotein complex forms cotranscriptionally in chromatin. SRSF3 depletion disrupts SRSF3-UPF1 axis, elevating the levels of p53β mRNA encoding a C-terminal-truncated isoform. Intriguitly, p53β protein isoform lacks tumor-suppressive activity and promotes oncogenic epithelial-mesenchymal transition through enhanced cell migration and invasion. We define the coordinated roles of the splicing factor SRSF3 and the RNA surveillance factor UPF1 in regulating p53 mRNA isoform expression, thereby linking splicing fidelity with RNA surveillance during transcription. Our findings highlight the SRSF3-UPF1 axis for preventing oncogenic p53β protein isoform accumulation, offering a potential therapeutic target to restore p53 function and impede cancer progression.