Splicing Correction as a Therapeutic Approach for Acetylation-Defective p53 K120R mutation
The TP53 c.359A>G mutation severely impairs expression of the major TP53 transcript variant encoding p53 K120R by creating a new splicing donor site. Antisense morpholino oligomer (AMO) targeting the mutation site restored normal splicing and expression of the major variant. Despite the recovery of mutant TP53 mRNA levels, the functional restoration as the tumor suppressor of p53 K120R was unclear. Given that p53 exerts its tumor suppressor function through regulation of target genes that mediate growth arrest or apoptosis, the p53 K120R mutant exhibits impaired transcriptional regulation of CDKN1A, a key target gene in growth arrest, while maintaining normal induction of the pro-apoptotic BBC3 gene. Consequently, the p53 K120R mutant protein demonstrates a phenotype characterized by defective cell growth arrest but retained apoptotic induction capacity, suggesting that the p53 K120R mutant protein may retain some tumor suppressor functionality. In addition, Lysine 120 provides a critical acetylation site linked to p53 activation. Although other studies of the oncogenic effects of p53 K120R highlight the relevance of acetylation for tumor suppression, our findings indicate that targeting mutant TP53 mRNA is a prerequisite for restoration of p53 function. In particular, despite the presence of mutations, it showed sufficient corrective effect to restore p53 functions, including apoptosis induction. In conclusion, this study highlights the potential of AMO-mediated splice correction as a therapeutic approach for TP53 mutations. Overall design: The splicing issue caused by the TP53 c.359A>G mutation was treated with an antisense morpholino oligonucleotide, and its effects were studied.