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However, <jats:italic>TP53<\/jats:italic> also encodes other protein isoforms, some of which can disrupt the tumor suppressor functions of p53 even in the absence of <jats:italic>TP53<\/jats:italic> mutations. In particular, elevated levels of the \u0394133<jats:italic>TP53<\/jats:italic> mRNA are detected in many cancer types and can be associated with poorer disease-free survival. We investigated the mechanisms of action of the two proteins translated from the \u0394133<jats:italic>TP53<\/jats:italic> mRNA: the \u0394133p53\u03b1 and \u0394160p53\u03b1 isoforms, both of which retain the oligomerization domain of p53. We discovered that the \u0394133p53\u03b1 and \u0394160p53\u03b1 isoforms adopt an altered conformation compared to full-length p53, exposing the PAb240 epitope (RHSVVV), which is inaccessible to the PAb240 antibody in the functional conformation of p53 (reactive to PAb1620). The \u0394133p53\u03b1 and\/or \u0394160p53\u03b1 isoforms form hetero-oligomers with p53, regulating the stability, the conformation and the transcriptional activity of the p53 hetero-oligomers. Under basal conditions, \u0394133p53\u03b1 and \u0394160p53\u03b1, in complex with p53, prevent proteasome-dependent degradation leading to the accumulation of PAb240 reactive \u0394133p53\u03b1\/\u0394160p53\u03b1\/p53 hetero-oligomers without increasing p53 transcriptional activity. Conversely, depletion of endogenous \u0394133p53\u03b1 isoforms in human fibroblasts is sufficient to restore p53 transcriptional activity, towards p53-target genes involved in cell cycle arrest. In the DNA damage response (DDR), PAb240 reactive \u0394133p53\u03b1\/\u0394160p53\u03b1\/p53 hetero-oligomers are highly phosphorylated at Ser15 compared to PAb1620-reactive p53 complexes devoid of \u0394133p53\u03b1 and \u0394160p53\u03b1. This suggests that PAb240-reactive p53 hetero-oligomers integrate DNA damage signals. \u0394133p53\u03b1 accumulation is a late event in the DDR that depends on p53, but not on its transcriptional activation. The formation of \u0394133p53\u03b1 and p53 complexes increases at later DDR stages. We propose that \u0394133p53\u03b1 isoforms regulate p53 conformation as part of the normal p53 biology, modulating p53 activity and thereby adapting the cellular response to the cell signals.<\/jats:p>","DOI":"10.1038\/s41419-024-07213-4","type":"journal-article","created":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T07:02:35Z","timestamp":1731999755000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Interaction of p53 with the \u0394133p53\u03b1 and \u0394160p53\u03b1 isoforms regulates p53 conformation and transcriptional activity"],"prefix":"10.1038","volume":"15","author":[{"given":"Fanny","family":"Tomas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Roux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9009-2185","authenticated-orcid":false,"given":"V\u00e9ronique","family":"Gire","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,11,19]]},"reference":[{"key":"7213_CR1","doi-asserted-by":"publisher","first-page":"7644","DOI":"10.1038\/sj.onc.1203015","volume":"18","author":"ND Lakin","year":"1999","unstructured":"Lakin ND, Jackson SP. 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