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EXOSC10's localization and stability are regulated by sumoylation and proteasomal degradation in response to stress, and the protein is essential for cell growth and proliferation, fertility, hematopoiesis, and brain development. EXOSC10 is a cancer biomarker; its activity is inhibited by the widely used anticancer drug 5\u2010fluorouracil (5\u2010FU) and the protein's depletion sensitizes cells to 5\u2010FU. We employed mass spectrometry to reveal EXOSC10's post\u2010translational modifications, such as phosphorylation, acetylation and ubiquitination, and to explore its protein interaction network, which includes RNA exosome subunits and enzymes involved in protein degradation. Furthermore, we find that the\n                    <jats:italic>EXOSC10<\/jats:italic>\n                    <jats:sup>S402T<\/jats:sup>\n                    allele identified in colon cancer and located within a motif for targeted proteolysis is stable, nuclear but nonfunctional\n                    <jats:italic>in vivo<\/jats:italic>\n                    , since homozygous\n                    <jats:italic>Exosc10<\/jats:italic>\n                    <jats:sup>S402T<\/jats:sup>\n                    mice exhibit early embryonic lethality. We identified equivalent S402P\/S402A variants and heterozygous loss\u2010of\u2010function (LoF) alleles in cancers and healthy individuals using public genomics data. Our findings suggest that recessive\n                    <jats:italic>EXOSC10<\/jats:italic>\n                    LoF alleles may cause increased 5\u2010FU sensitivity in tumors bearing\n                    <jats:italic>de novo<\/jats:italic>\n                    mutations and hypertoxicity in heterozygous carriers.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.70239","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T09:43:29Z","timestamp":1778838209000},"page":"1913-1932","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Heterozygous loss\u2010of\u2010function alleles associate the conserved 3\u2032\u20105\u2032 exoribonuclease\n                    <scp>EXOSC10<\/scp>\n                    with hypersensitivity to the anticancer drug 5\u2010fluorouracil"],"prefix":"10.1002","volume":"20","author":[{"given":"Radhika","family":"Sain","sequence":"first","affiliation":[{"name":"Inserm, EHESP, Irset (Institut de recherche en sant\u00e9, environnement et travail) \u2010 UMR_S 1085 Univ Rennes  Rennes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yann","family":"Le Page","sequence":"additional","affiliation":[{"name":"Inserm, EHESP, Irset (Institut de recherche en sant\u00e9, environnement et travail) \u2010 UMR_S 1085 Univ Rennes  Rennes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Percevault","sequence":"additional","affiliation":[{"name":"Inserm, EHESP, Irset (Institut de recherche en sant\u00e9, environnement et travail) \u2010 UMR_S 1085 Univ Rennes  Rennes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuelle","family":"Becker","sequence":"additional","affiliation":[{"name":"Inserm, EHESP, Irset (Institut de recherche en sant\u00e9, environnement et travail) \u2010 UMR_S 1085 Univ Rennes  Rennes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc","family":"Negroni","sequence":"additional","affiliation":[{"name":"ESBS, \u2010BCS\u2010UMR7242  Illkirch France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Almudena","family":"Fernandez","sequence":"additional","affiliation":[{"name":"National Centre of Biotechnology (CNB\u2010CSIC)  Madrid Spain"},{"name":"Biomedical Research Networking Center on Rare Diseases (CIBERER\u2010ISCIII)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Cantero","sequence":"additional","affiliation":[{"name":"National Centre of Biotechnology (CNB\u2010CSIC)  Madrid Spain"},{"name":"Biomedical Research Networking Center on Rare Diseases (CIBERER\u2010ISCIII)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Mu\u00f1oz\u2010Santos","sequence":"additional","affiliation":[{"name":"National Centre of Biotechnology (CNB\u2010CSIC)  Madrid Spain"},{"name":"Biomedical Research Networking Center on Rare Diseases (CIBERER\u2010ISCIII)  Madrid Spain"},{"name":"Department of Medicine. Faculty of Medicine, Health and Sports Universidad Europea de Madrid  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Llu\u00eds","family":"Montoliu","sequence":"additional","affiliation":[{"name":"National Centre of Biotechnology (CNB\u2010CSIC)  Madrid Spain"},{"name":"Biomedical Research Networking Center on Rare Diseases (CIBERER\u2010ISCIII)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyrille","family":"Garnier","sequence":"additional","affiliation":[{"name":"Inserm, EHESP, Irset (Institut de recherche en sant\u00e9, environnement et travail) \u2010 UMR_S 1085 Univ Rennes  Rennes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2061-0119","authenticated-orcid":false,"given":"Michael","family":"Primig","sequence":"additional","affiliation":[{"name":"Inserm, EHESP, Irset (Institut de recherche en sant\u00e9, environnement et travail) \u2010 UMR_S 1085 Univ Rennes  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