{"entity": "researcher", "timestamp": "2026-08-26T05:41:13.981Z", "family": "Joerger", "given": "Andreas C", "initials": "AC", "orcid": "0000-0002-1232-0138", "affiliations": ["Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt am Main, Germany. joerger@pharmchem.uni-frankfurt.de.", "Structural Genomics Consortium (SGC), Buchmann Institute for Molecular Life Sciences, Frankfurt am Main, Germany. joerger@pharmchem.uni-frankfurt.de."], "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/researcher/b8697067e0864557a0876d9cf5fe465b.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/researcher/b8697067e0864557a0876d9cf5fe465b"}}, "publications": [{"entity": "publication", "iuid": "97f93e66147b4692a7ed08081ecef5ba", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/97f93e66147b4692a7ed08081ecef5ba.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/97f93e66147b4692a7ed08081ecef5ba"}}, "title": "TP53: the unluckiest of genes?", "authors": [{"family": "Joerger", "given": "Andreas C", "initials": "AC", "orcid": "0000-0002-1232-0138", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/b8697067e0864557a0876d9cf5fe465b.json"}}, {"family": "Stiewe", "given": "Thorsten", "initials": "T", "orcid": "0000-0003-0134-7826", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/b11b87211f0043faaebdd9771e49c01c.json"}}, {"family": "Soussi", "given": "Thierry", "initials": "T"}], "type": "journal article", "published": "2025-02-00", "journal": {"title": "Cell Death Differ.", "issn": "1476-5403", "volume": "32", "issue": "2", "pages": "219-224", "issn-l": "1350-9047"}, "abstract": "The transcription factor p53 plays a key role in the cellular defense against cancer development. It is inactivated in virtually every tumor, and in every second tumor this inactivation is due to a mutation in the TP53 gene. In this perspective, we show that this diverse mutational spectrum is unique among all other cancer-associated proteins and discuss what drives the selection of TP53 mutations in cancer. We highlight that several factors conspire to make the p53 protein particularly vulnerable to inactivation by the mutations that constantly plague our genome. It appears that the TP53 gene has emerged as a victim of its own evolutionary past that shaped its structure and function towards a pluripotent tumor suppressor, but came with an increased structural fragility of its DNA-binding domain. TP53 loss of function - with associated dominant-negative effects - is the main mechanism that will impair TP53 tumor suppressive function, regardless of whether a neomorphic phenotype is associated with some of these variants.", "doi": "10.1038/s41418-024-01391-6", "pmid": "39443700", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC11803090"}, {"db": "pii", "key": "10.1038/s41418-024-01391-6"}], "notes": [], "created": "2026-08-21T11:47:36.781Z", "modified": "2026-08-21T11:47:36.882Z"}, {"entity": "publication", "iuid": "17437f73a01845e696eeb3c2a940d249", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/17437f73a01845e696eeb3c2a940d249.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/17437f73a01845e696eeb3c2a940d249"}}, "title": "Deep CRISPR mutagenesis characterizes the functional diversity of TP53 mutations.", "authors": [{"family": "Funk", "given": "Julianne S", "initials": "JS", "orcid": "0000-0002-1848-7975", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/553a165f21874a9fbe6fe5ce2c0b14e2.json"}}, {"family": "Klimovich", "given": "Maria", "initials": "M"}, {"family": "Drangenstein", "given": "Daniel", "initials": "D"}, {"family": "Pielhoop", "given": "Ole", "initials": "O"}, {"family": "Hunold", "given": "Pascal", "initials": "P", "orcid": "0000-0002-7087-5908", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/de644feeafe347caaace23249fcc924a.json"}}, {"family": "Borowek", "given": "Anna", "initials": "A"}, {"family": "Noeparast", "given": "Maxim", "initials": "M", "orcid": "0000-0002-3216-5630", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/c44b044eb1cd4cfdb441fe471593bee5.json"}}, {"family": "Pavlakis", "given": "Evangelos", "initials": "E"}, {"family": "Neumann", "given": "Michelle", "initials": "M"}, {"family": "Balourdas", "given": "Dimitrios-Ilias", "initials": "DI", "orcid": "0000-0002-1790-2268", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/bb44c08b0a624b8c827cfc52af368088.json"}}, {"family": "Kochhan", "given": "Katharina", "initials": "K"}, {"family": "Merle", "given": "Nastasja", "initials": "N"}, {"family": "Bullwinkel", "given": "Imke", "initials": "I"}, {"family": "Wanzel", "given": "Michael", "initials": "M"}, {"family": "Elmsh\u00e4user", "given": "Sabrina", "initials": "S"}, {"family": "Teply-Szymanski", "given": "Julia", "initials": "J"}, {"family": "Nist", "given": "Andrea", "initials": "A"}, {"family": "Procida", "given": "Tara", "initials": "T"}, {"family": "Bartkuhn", "given": "Marek", "initials": "M", "orcid": "0000-0001-6872-9082", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/5f9df033a2d34799b586f77d6ac72024.json"}}, {"family": "Humpert", "given": "Katharina", "initials": "K"}, {"family": "Mernberger", "given": "Marco", "initials": "M"}, {"family": "Savai", "given": "Rajkumar", "initials": "R", "orcid": "0000-0003-1538-2091", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/b4dfb5d2135a448390ae240d4b4a516e.json"}}, {"family": "Soussi", "given": "Thierry", "initials": "T", "orcid": "0000-0001-8184-3293", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/fe0e1f55362244f6a482f8a71c9ec943.json"}}, {"family": "Joerger", "given": "Andreas C", "initials": "AC", "orcid": "0000-0002-1232-0138", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/b8697067e0864557a0876d9cf5fe465b.json"}}, {"family": "Stiewe", "given": "Thorsten", "initials": "T", "orcid": "0000-0003-0134-7826", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/b11b87211f0043faaebdd9771e49c01c.json"}}], "type": "journal article", "published": "2025-01-00", "journal": {"title": "Nat. Genet.", "issn": "1546-1718", "volume": "57", "issue": "1", "pages": "140-153", "issn-l": "1061-4036"}, "abstract": "The mutational landscape of TP53, a tumor suppressor mutated in about half of all cancers, includes over 2,000 known missense mutations. To fully leverage TP53 mutation status for personalized medicine, a thorough understanding of the functional diversity of these mutations is essential. We conducted a deep mutational scan using saturation genome editing with CRISPR-mediated homology-directed repair to engineer 9,225 TP53 variants in cancer cells. This high-resolution approach, covering 94.5% of all cancer-associated TP53 missense mutations, precisely mapped the impact of individual mutations on tumor cell fitness, surpassing previous deep mutational scan studies in distinguishing benign from pathogenic variants. Our results revealed even subtle loss-of-function phenotypes and identified promising mutants for pharmacological reactivation. Moreover, we uncovered the roles of splicing alterations and nonsense-mediated messenger RNA decay in mutation-driven TP53 dysfunction. These findings underscore the power of saturation genome editing in advancing clinical TP53 variant interpretation for genetic counseling and personalized cancer therapy.", "doi": "10.1038/s41588-024-02039-4", "pmid": "39774325", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC11735402"}, {"db": "pii", "key": "10.1038/s41588-024-02039-4"}], "notes": [], "created": "2026-08-21T11:51:49.324Z", "modified": "2026-08-21T11:51:49.624Z"}]}