Antisense-mediated splicing correction as a therapeutic approach for p53 K120R mutation
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The TP53 c.359A＞G mutation significantly disrupts the expressionof the major TP53 transcript variant encoding p53 K120R bygenerating a new splice donor site. An antisense morpholinooligomer (AMO) targeting this mutation successfully restorednormal splicing and the expression of the major TP53 variant. Given that p53 exerts its tumor suppressor function by regulatingtarget genes responsible for growth arrest or apoptosis,the p53 K120R protein enhanced by AMO exhibits impairedtranscriptional regulation of CDKN1A, a key growth arrest gene,while maintaining normal induction of the pro-apoptotic BBC3gene. As a result, the mutant p53 K120R protein shows adefective cell growth arrest phenotype but retains apoptotic function,suggesting that it may still possess some tumor suppressoractivity. Furthermore, lysine 120, known to provide a criticalacetylation site for p53 activation, highlights the relevance ofacetylation in tumor suppression through studies of the p53K120R mutant. However, our findings demonstrate that targetingmutant TP53 mRNA with AMO is essential for restoring p53function. In conclusion, this study emphasizes the potential ofAMO-mediated splice correction as a therapeutic approach forTP53 mutations.
Abstract
The TP53 c.359A＞G mutation significantly disrupts the expressionof the major TP53 transcript variant encoding p53 K120R bygenerating a new splice donor site. An antisense morpholinooligomer (AMO) targeting this mutation successfully restorednormal splicing and the expression of the major TP53 variant. Given that p53 exerts its tumor suppressor function by regulatingtarget genes responsible for growth arrest or apoptosis,the p53 K120R protein enhanced by AMO exhibits impairedtranscriptional regulation of CDKN1A, a key growth arrest gene,while maintaining normal induction of the pro-apoptotic BBC3gene. As a result, the mutant p53 K120R protein shows adefective cell growth arrest phenotype but retains apoptotic function,suggesting that it may still possess some tumor suppressoractivity. Furthermore, lysine 120, known to provide a criticalacetylation site for p53 activation, highlights the relevance ofacetylation in tumor suppression through studies of the p53K120R mutant. However, our findings demonstrate that targetingmutant TP53 mRNA with AMO is essential for restoring p53function. In conclusion, this study emphasizes the potential ofAMO-mediated splice correction as a therapeutic approach forTP53 mutations.
참고문헌 (26)
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