Conserved Double Translation Initiation Site for Δ160p53 Protein Hints at Isoform's Key Role in Mammalian Physiology

This article belongs to the Special Issue p53 in Cancer and beyond—40 Years after Its Discoveryp53 is the most commonly mutated gene in human cancers. Two fundamental reasons for this are its long protein isoforms protect from cancer, while its shorter C-terminal isoforms can support cancer and metastasis. Previously, we have shown that the Δ160p53 protein isoform enhances survival and the invasive character of cancer cells. Here, we identified a translation initiation site nine codons downstream of codon 160-the known initiation codon for the translation of Δ160p53-that is recognized by the translation machinery. When translation failed to initiate from AUG160 due to mutation, it initiated from AUG169 instead, producing similar levels of a similar protein, Δ169p53, which promoted cell survival as efficiently as Δ160p53 following DNA damage. Interestingly, almost all mammalian species with an orthologue to human AUG160 also possess one for AUG169, while none of the non-mammalian species lacking AUG160 have AUG169, even if that region of the p53 gene is well conserved. In view of our findings, we do not believe that Δ169p53 acts as a different p53 protein isoform; instead, we propose that the double translation initiation site strengthens the translation of these products with a critical role in cell homeostasis. Future studies will help verify if this is a more general mechanism for the expression of essential proteins in mammals.This research was funded by grants 18K07229 (KAKENHI) from Japan Society for the Promotion of Science (JSPS), PTDC/BIM-ONC/4890/2014 and PTDC/MED-ONC/32048/2017 from Fundação para a Ciência e a Tecnologia of Portugal (FCT) and grants/fellowships from Takeda Science Foundation (2017 Medical Research Fellowship (Oncology, Basic)), Astellas Research Foundation for Pathophysiology and Metabolism (project number 203180600044), AXA Research Fund, Ichiro Kanehara Foundation and Kyoto University (Ishizue, year 2021) attributed to M.M.C. This work was also partially supported by grant UID/MULTI/04046/2013 to BioISI from FCT/MCTES/PIDDAC and by funds from Instituto Nacional de Saúde Doutor Ricardo Jorge. M.J.L.I. and S.N.P. were partially supported by Otsuka Toshimi Scholarship Foundation. ACR is the recipient of a PhD scholarship from the Portuguese Foundation for Science and Technology (2020.06982.BD)