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An alteration or malfunction in\n                    <jats:italic>p53<\/jats:italic>\n                    may lead to cancer, degeneration or premature ageing. So, it is not surprising that\n                    <jats:italic>p53<\/jats:italic>\n                    is also one of the most complex and tightly regulated genes, encoding for at least 10 RNA variants and 12 widely accepted protein forms. Here we identify one new p53 protein isoform of approximately 18\u2009kDa that we termed \u0394246p53. \u0394246p53 is translated from an alternative translation initiation site (TIS) at codon 246. TIS-246 is preceded by a strong Kozak sequence and appears conserved in vertebrates, from sea lamprey to humans. \u0394246p53\u2019s origin and expression in cells were confirmed by frameshift and start codon mutations; five different antibodies against epitopes spanning its N- to C-terminus, as well as an antibody against the DNA-binding domain region just upstream of its initiator methionine, which served as a negative control; and\u00a0siRNAs and an antisense oligo targeting TIS-246, which knocked down \u0394246p53 with little or no effect on full-length (FL) p53 protein levels. \u0394246p53 was induced by DNA damage and triggered senescence and impaired tumour formation\/growth in colony formation assays. Mechanistically, \u0394246p53 interacted with FLp53, leading to a decrease in the expression of downstream target genes\n                    <jats:italic>HDM2<\/jats:italic>\n                    and\n                    <jats:italic>p21<\/jats:italic>\n                    . Concurrently, it also interacted with \u0394Np63, leading to\n                    <jats:italic>p53<\/jats:italic>\n                    -independent\n                    <jats:italic>p63<\/jats:italic>\n                    -mediated activation of\n                    <jats:italic>p21<\/jats:italic>\n                    , a known senescence activator. Our results unveil a new naturally occurring and tightly controlled factor with specific functions in\n                    <jats:italic>p21<\/jats:italic>\n                    regulation and senescence. Future studies on \u0394246p53 are likely to help us better understand and control the processes of tumour suppression and ageing.\n                  <\/jats:p>","DOI":"10.1038\/s41420-026-03374-7","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T10:04:26Z","timestamp":1791367466000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["New \u0394246p53 isoform responds to DNA damage to enhance p53 family functions in cellular senescence"],"prefix":"10.1038","author":[{"given":"Shrutee N.","family":"Parkar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0296-8632","authenticated-orcid":false,"given":"Ana Catarina","family":"Ramalho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6345-5617","authenticated-orcid":false,"given":"Maria Jos\u00e9","family":"L\u00f3pez-Iniesta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyuan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koto","family":"Kimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Dassi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filipa","family":"da Silva Rita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9231-379X","authenticated-orcid":false,"given":"Yari","family":"Ciribilli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3326-1923","authenticated-orcid":false,"given":"Alessandra","family":"Bisio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5061-5287","authenticated-orcid":false,"given":"Lu\u00edsa","family":"Rom\u00e3o","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5731-0179","authenticated-orcid":false,"given":"Marco M.","family":"Candeias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,7]]},"container-title":["Cell Death Discovery"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41420-026-03374-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T10:04:27Z","timestamp":1791367467000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41420-026-03374-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,7]]},"references-count":0,"alternative-id":["3374"],"URL":"https:\/\/doi.org\/10.1038\/s41420-026-03374-7","relation":{},"ISSN":["2058-7716"],"issn-type":[{"value":"2058-7716","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,7]]},"assertion":[{"value":"24 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 August 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 September 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 October 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"The study was approved by the Safety and Health Division of the Graduate School of Medicine of Kyoto University (#250156). All methods were carried out in accordance with the relevant guidelines and regulations. The study was performed in accordance with the Cartagena Protocol on Biosafety.","order":2,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Ethics"}}]}}