Therapeutic targeting of TP53 nonsense mutations in cancer

Abstract

Mutations in the TP53 tumor suppressor gene occur with high prevalence in a wide range of human tumors. A significant fraction of these mutations (around 10%) are nonsense mutations, creating a premature termination codon (PTC) that leads to the expression of truncated inactive p53 protein. Induction of translational readthrough across a PTC in nonsense mutant TP53 allows the production of full-length protein and potentially restoration of normal p53 function. Aminoglycoside antibiotics and a number of novel compounds have been shown to induce full-length p53 in tumor cells carrying various TP53 nonsense mutations. Full-length p53 protein generated by translational readthrough retains the capacity to transactivate p53 target genes and trigger tumor cell death. These findings raise hopes for efficient therapy of TP53 nonsense mutant tumors in the future.

Keywords: TP53; cancer therapy; nonsense mutations; translational readthrough.

Figure 1

Overview of translational readthrough. (a) Translation is stalled when the ribosome reaches a premature termination codon (PTC) in the mRNA. Release factors eRF1 and eRF3 bind and translation is prematurely terminated, causing the release of a truncated non-functional protein. (b) Aminoglycoside antibiotics and other readthrough-inducing agents can suppress the PTC by enabling misincorporation of a near-cognate aminoacyl-tRNA. (c) Readthrough induction allows the ribosome to continue translation across the PTC until the normal stop codon, resulting in the production of a full-length protein.

Figure 2

TP53 nonsense mutation spectrum in cancer. Bars indicate nonsense mutations in the TP53 coding sequence. Around 10% of all TP53 mutations are nonsense mutations. The five most common nonsense mutations are indicated. TP53 nonsense mutations are distributed over most of the p53 coding sequence, in contrast to missense mutations that cluster in the DNA-binding core domain (not shown). The p53 protein (393 amino acid residues) is shown schematically with structural domains: N-terminal transactivation domains (TAD, blue), proline-rich domain (PRD, purple), DNA-binding domain (DBD, green), tetramerization domain (TED, yellow), and C-terminal oligomerization domain (CTD, red). Data were collected from the COSMIC database (6 April 2024, cancer.sanger.ac.uk).