Loss of p62 binding allows TIF-IA accumulation in senescence, which promotes phenotypic changes to nucleoli and the senescence associated secretory phenotype

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 com...

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Autores: Thoms, Hazel S., Brant, Tyler S., Duckett, Katie, Yang, Yizheng, Dong, Jinxi, Wang, Hongfei, Derby, Freya, Akeke, Oluwatumilara F., Al-Alayeen, Faizah, Newell, Amy, Manasterski, Piotr, Gopalakrishnan, Aishwarya, Mann, Derek, Millar, Fraser R., Kriegsheim, Alex Von, Acosta Cobacho, Juan Carlos, Oakley, Fiona, Stark, Lesley A.
Tipo de recurso: artículo
Fecha de publicación:2026
País:España
Institución:Universidad de Cantabria (UC)
Repositorio:UCrea Repositorio Abierto de la Universidad de Cantabria
Idioma:inglés
OAI Identifier:oai:dnet:ucreareposit::6b677c572632863d8b57ac741a6a05af
Acceso en línea:https://hdl.handle.net/10902/40171
Access Level:acceso abierto
Palabra clave:ATM
DNA damage
Inflammation
Nucleolar
Nucleolus
p62
Poll complex
ROS
Senescence
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spelling Loss of p62 binding allows TIF-IA accumulation in senescence, which promotes phenotypic changes to nucleoli and the senescence associated secretory phenotypeThoms, Hazel S.Brant, Tyler S.Duckett, KatieYang, YizhengDong, JinxiWang, HongfeiDerby, FreyaAkeke, Oluwatumilara F.Al-Alayeen, FaizahNewell, AmyManasterski, PiotrGopalakrishnan, AishwaryaMann, DerekMillar, Fraser R.Kriegsheim, Alex VonAcosta Cobacho, Juan CarlosOakley, FionaStark, Lesley A.ATMDNA damageInflammationNucleolarNucleolusp62Poll complexROSSenescenceA 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.The work was funded by BBSRC (BB/S018530/1), Worldwide Cancer Research (25- 0415) and Rosetrees Trust (A631, JS16/M225) to L.A.S. and CRUK (C18342/A23390) to F.O and D.MWileyUniversidad de Cantabria20262026-01-01journal articlehttp://purl.org/coar/resource_type/c_6501NAhttp://purl.org/coar/version/c_be7fb7dd8ff6fe43info:eu-repo/semantics/articlehttps://hdl.handle.net/10902/40171Aging Cell, 2025, 25(1), e70334reponame:UCrea Repositorio Abierto de la Universidad de Cantabriainstname:Universidad de Cantabria (UC)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:dnet:ucreareposit::6b677c572632863d8b57ac741a6a05af2026-06-02T12:39:31Z
dc.title.none.fl_str_mv Loss of p62 binding allows TIF-IA accumulation in senescence, which promotes phenotypic changes to nucleoli and the senescence associated secretory phenotype
title Loss of p62 binding allows TIF-IA accumulation in senescence, which promotes phenotypic changes to nucleoli and the senescence associated secretory phenotype
spellingShingle Loss of p62 binding allows TIF-IA accumulation in senescence, which promotes phenotypic changes to nucleoli and the senescence associated secretory phenotype
Thoms, Hazel S.
ATM
DNA damage
Inflammation
Nucleolar
Nucleolus
p62
Poll complex
ROS
Senescence
title_short Loss of p62 binding allows TIF-IA accumulation in senescence, which promotes phenotypic changes to nucleoli and the senescence associated secretory phenotype
title_full Loss of p62 binding allows TIF-IA accumulation in senescence, which promotes phenotypic changes to nucleoli and the senescence associated secretory phenotype
title_fullStr Loss of p62 binding allows TIF-IA accumulation in senescence, which promotes phenotypic changes to nucleoli and the senescence associated secretory phenotype
title_full_unstemmed Loss of p62 binding allows TIF-IA accumulation in senescence, which promotes phenotypic changes to nucleoli and the senescence associated secretory phenotype
title_sort Loss of p62 binding allows TIF-IA accumulation in senescence, which promotes phenotypic changes to nucleoli and the senescence associated secretory phenotype
dc.creator.none.fl_str_mv Thoms, Hazel S.
Brant, Tyler S.
Duckett, Katie
Yang, Yizheng
Dong, Jinxi
Wang, Hongfei
Derby, Freya
Akeke, Oluwatumilara F.
Al-Alayeen, Faizah
Newell, Amy
Manasterski, Piotr
Gopalakrishnan, Aishwarya
Mann, Derek
Millar, Fraser R.
Kriegsheim, Alex Von
Acosta Cobacho, Juan Carlos
Oakley, Fiona
Stark, Lesley A.
author Thoms, Hazel S.
author_facet Thoms, Hazel S.
Brant, Tyler S.
Duckett, Katie
Yang, Yizheng
Dong, Jinxi
Wang, Hongfei
Derby, Freya
Akeke, Oluwatumilara F.
Al-Alayeen, Faizah
Newell, Amy
Manasterski, Piotr
Gopalakrishnan, Aishwarya
Mann, Derek
Millar, Fraser R.
Kriegsheim, Alex Von
Acosta Cobacho, Juan Carlos
Oakley, Fiona
Stark, Lesley A.
author_role author
author2 Brant, Tyler S.
Duckett, Katie
Yang, Yizheng
Dong, Jinxi
Wang, Hongfei
Derby, Freya
Akeke, Oluwatumilara F.
Al-Alayeen, Faizah
Newell, Amy
Manasterski, Piotr
Gopalakrishnan, Aishwarya
Mann, Derek
Millar, Fraser R.
Kriegsheim, Alex Von
Acosta Cobacho, Juan Carlos
Oakley, Fiona
Stark, Lesley A.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidad de Cantabria
dc.subject.none.fl_str_mv ATM
DNA damage
Inflammation
Nucleolar
Nucleolus
p62
Poll complex
ROS
Senescence
topic ATM
DNA damage
Inflammation
Nucleolar
Nucleolus
p62
Poll complex
ROS
Senescence
description 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.
publishDate 2026
dc.date.none.fl_str_mv 2026
2026-01-01
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
NA
http://purl.org/coar/version/c_be7fb7dd8ff6fe43
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/10902/40171
url https://hdl.handle.net/10902/40171
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Wiley
publisher.none.fl_str_mv Wiley
dc.source.none.fl_str_mv Aging Cell, 2025, 25(1), e70334
reponame:UCrea Repositorio Abierto de la Universidad de Cantabria
instname:Universidad de Cantabria (UC)
instname_str Universidad de Cantabria (UC)
reponame_str UCrea Repositorio Abierto de la Universidad de Cantabria
collection UCrea Repositorio Abierto de la Universidad de Cantabria
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.811543

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