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Although a number of pathways have been suggested, the mechanisms underlying this altered nucleolar phenotype, and the downstream consequences, remain poorly understood. The PolI complex component, TIF\u2010IA, has previously been implicated in regulating this characteristic nucleolar phenotype in response to stress. Here we explored the role of TIF\u2010IA in senescence and ageing. We show that TIF\u2010IA accumulation, particularly in the nucleus and nucleolus, is an early response to oncogene\u2010 and therapy\u2010induced senescence (OIS and TIS) in\u00a0vitro. Using multiple mouse models, we also demonstrate accumulation of TIF\u2010IA in response to senescence induction and ageing in\u00a0vivo. We demonstrate that TIF\u2010IA accumulation is not required for cell cycle arrest but that in OIS and TIS, it is essential for phenotypic changes to nucleoli, the senescence\u2010associated secretory phenotype (SASP) and establishment of stable senescence. We demonstrate that in proliferating cells, TIF\u2010IA binds the cargo receptor, p62 (SQSTM1), and that accumulation in senescence occurs as a consequence of ATM activation, which disrupts this interaction. Finally, we show that TIF\u2010IA accumulation causes an increase in reactive oxygen species (ROS) levels. Together, these results establish TIF\u2010IA accumulation as a key regulator of the nucleolar phenotype and the SASP in senescence and uncover a novel, p62\u2010dependent mechanism driving this process. These findings offer significant new insights into nucleolar size regulation in senescence and ageing, and suggest a potential relationship with the inflammatory phenotype.<\/jats:p>","DOI":"10.1111\/acel.70334","type":"journal-article","created":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T05:47:26Z","timestamp":1767073646000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Loss of p62 Binding Allows\n                    <scp>TIF<\/scp>\n                    \u2010\n                    <scp>IA<\/scp>\n                    Accumulation in Senescence, Which Promotes Phenotypic Changes to Nucleoli and the Senescence Associated Secretory Phenotype"],"prefix":"10.1111","volume":"25","author":[{"given":"Hazel C.","family":"Thoms","sequence":"first","affiliation":[{"name":"Edinburgh Cancer Research Centre, Institute of Genetics and Cancer (IGC) University of Edinburgh  Edinburgh 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Centre, Institute of Genetics and Cancer (IGC) University of Edinburgh  Edinburgh UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongfei","family":"Wang","sequence":"additional","affiliation":[{"name":"Edinburgh Cancer Research Centre, Institute of Genetics and Cancer (IGC) University of Edinburgh  Edinburgh UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Freya","family":"Derby","sequence":"additional","affiliation":[{"name":"Edinburgh Cancer Research Centre, Institute of Genetics and Cancer (IGC) University of Edinburgh  Edinburgh UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oluwatumilara F.","family":"Akeke","sequence":"additional","affiliation":[{"name":"Edinburgh Cancer Research Centre, Institute of Genetics and Cancer (IGC) University of Edinburgh  Edinburgh UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Faizah","family":"Al\u2010Alayeen","sequence":"additional","affiliation":[{"name":"Edinburgh Cancer Research Centre, Institute of Genetics and Cancer (IGC) University of Edinburgh  Edinburgh UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amy","family":"Newell","sequence":"additional","affiliation":[{"name":"Edinburgh Cancer Research Centre, Institute of Genetics and Cancer (IGC) University of Edinburgh  Edinburgh UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Piotr","family":"Manasterski","sequence":"additional","affiliation":[{"name":"Edinburgh Cancer Research Centre, Institute of Genetics and Cancer (IGC) University of Edinburgh  Edinburgh UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aishwarya","family":"Gopalakrishnan","sequence":"additional","affiliation":[{"name":"Edinburgh Cancer Research Centre, Institute of Genetics and Cancer (IGC) University of Edinburgh  Edinburgh 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Institute of Genetics and Cancer (IGC) University of Edinburgh  Edinburgh UK"},{"name":"Instituto de Biomedicina y Biotecnolog\u00eda de Cantabria (IBBTEC), CSIC\u2010Universidad de Cantabria  Santander Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8692-1836","authenticated-orcid":false,"given":"Fiona","family":"Oakley","sequence":"additional","affiliation":[{"name":"Biosciences Institute, Faculty of Medical Sciences Newcastle University  Newcastle Upon Tyne UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8451-7191","authenticated-orcid":false,"given":"Lesley A.","family":"Stark","sequence":"additional","affiliation":[{"name":"Edinburgh Cancer Research Centre, Institute of Genetics and Cancer (IGC) University of Edinburgh  Edinburgh 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