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Lookup NU author(s): Professor Derek MannORCiD, Professor Fiona OakleyORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2025 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.A key characteristic of senescent and ageing cells is a reduction in number and increase in size of nucleoli. 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-IA, has previously been implicated in regulating this characteristic nucleolar phenotype in response to stress. Here we explored the role of TIF-IA in senescence and ageing. We show that TIF-IA accumulation, particularly in the nucleus and nucleolus, is an early response to oncogene- and therapy-induced senescence (OIS and TIS) in vitro. Using multiple mouse models, we also demonstrate accumulation of TIF-IA in response to senescence induction and ageing in vivo. We demonstrate that TIF-IA accumulation is not required for cell cycle arrest but that in OIS and TIS, it is essential for phenotypic changes to nucleoli, the senescence-associated secretory phenotype (SASP) and establishment of stable senescence. We demonstrate that in proliferating cells, TIF-IA 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-IA accumulation causes an increase in reactive oxygen species (ROS) levels. Together, these results establish TIF-IA accumulation as a key regulator of the nucleolar phenotype and the SASP in senescence and uncover a novel, p62-dependent 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.
Author(s): Thoms HC, Brant TS, Duckett K, Yang Y, Dong J, Wang H, Derby F, Akeke OF, Al-Alayeen F, Newell A, Manasterski P, Gopalakrishnan A, Mann D, Millar FR, Von Kriegsheim A, Acosta JC, Oakley F, Stark LA
Publication type: Article
Publication status: Published
Journal: Aging Cell
Year: 2026
Volume: 25
Issue: 1
Print publication date: 01/01/2026
Online publication date: 29/12/2025
Acceptance date: 07/12/2025
Date deposited: 12/01/2026
ISSN (print): 1474-9718
ISSN (electronic): 1474-9726
Publisher: John Wiley and Sons Inc
URL: https://doi.org/10.1111/acel.70334
DOI: 10.1111/acel.70334
Data Access Statement: The data underlying this article will be shared on reasonable request to the corresponding author.
PubMed id: 41466483
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