TPR is required for cytoplasmic chromatin fragment formation during senescence

During oncogene-induced senescence there are striking changes in the organisation of heterochromatin in the nucleus. This is accompanied by activation of a pro-inflammatory gene expression programme - the senescence-associated secretory phenotype (SASP) - driven by transcription factors such as NF-κ...

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Autores: Bartlett, Bethany M., Kumar, Yatendra, Boyle, Shelagh, Chowdhury, Tamoghna, Quintanilla Cavia, Andrea, Boumendil, Charlene, Acosta Cobacho, Juan Carlos, Bickmore, Wendy A.
Formato: artículo
Fecha de publicación:2024
País:España
Recursos:Universidad de Cantabria (UC)
Repositorio:UCrea Repositorio Abierto de la Universidad de Cantabria
Idioma:inglés
OAI Identifier:oai:repositorio.unican.es:10902/36499
Acesso em linha:https://hdl.handle.net/10902/36499
Access Level:acceso abierto
Palavra-chave:Cell biology
Chromosomes
Gene expression
Genome integrity
Heterochromatin
Human
Inflammation
Nuclear periphery
Oncogene
Senescence
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spelling TPR is required for cytoplasmic chromatin fragment formation during senescenceBartlett, Bethany M.Kumar, YatendraBoyle, ShelaghChowdhury, TamoghnaQuintanilla Cavia, AndreaBoumendil, CharleneAcosta Cobacho, Juan CarlosBickmore, Wendy A.Cell biologyChromosomesGene expressionGenome integrityHeterochromatinHumanInflammationNuclear peripheryOncogeneSenescenceDuring oncogene-induced senescence there are striking changes in the organisation of heterochromatin in the nucleus. This is accompanied by activation of a pro-inflammatory gene expression programme - the senescence-associated secretory phenotype (SASP) - driven by transcription factors such as NF-κB. The relationship between heterochromatin re-organisation and the SASP has been unclear. Here, we show that TPR, a protein of the nuclear pore complex basket required for heterochromatin re-organisation during senescence, is also required for the very early activation of NF-κB signalling during the stress-response phase of oncogene-induced senescence. This is prior to activation of the SASP and occurs without affecting NF-κB nuclear import. We show that TPR is required for the activation of innate immune signalling at these early stages of senescence and we link this to the formation of heterochromatin-enriched cytoplasmic chromatin fragments thought to bleb off from the nuclear periphery. We show that HMGA1 is also required for cytoplasmic chromatin fragment formation. Together these data suggest that re-organisation of heterochromatin is involved in altered structural integrity of the nuclear periphery during senescence, and that this can lead to activation of cytoplasmic nucleic acid sensing, NF-κB signalling, and activation of the SASP.Acknowledgments: We thank the Edinburgh Clinical Research Facility for RNA-seq library preparation and for the sequencing of RNA-seq and ATAC-seq libraries, and the IGC Advanced Imaging facility for their help in fluorescence imaging and image analysis. We are grateful to Marie-Therese El-Daher, IGC, for help with ELISA. Funding Statement: BMB was supported a PhD studentship from the Medical Research Council. YK and WAB were supported by a Wellcome Trust Investigator Award 217120/Z/19/Z. Work in the WAB lab is funded by MRC University Unit grants MC_UU_00007/2 and MC_UU_00035/7. JCA acknowledges funding by Cancer Research UK (CRUK) (C47559/A16243 Training & Career Development Board – Career Development Fellowship), the University of Edinburgh-MRC Chancellor’s Fellowship, the Ministry of Science and Innovation of the Government of Spain (Proyecto PID2020- 117860GB-I00 financed by MCIN/ AEI /10.13039/501100011033) and the Spanish National Research Council (CSIC). Work in the laboratory of CB is supported by the Centre national de la recherche scientifique (CNRS), the Agence Nationale de la Recherche (ANR), under grant number ANR-21- CE12-0039 (project NPCOS), and the French State within the Plan d’investissements France 2030 (program LabUM EpiGenMed, project ChOICe).Universidad de Cantabria20242024-01-01journal articlehttp://purl.org/coar/resource_type/c_6501NAhttp://purl.org/coar/version/c_be7fb7dd8ff6fe43info:eu-repo/semantics/articlehttps://hdl.handle.net/10902/36499eLife, 2024, 3(13), e101702reponame: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:repositorio.unican.es:10902/364992026-06-02T12:39:31Z
dc.title.none.fl_str_mv TPR is required for cytoplasmic chromatin fragment formation during senescence
title TPR is required for cytoplasmic chromatin fragment formation during senescence
spellingShingle TPR is required for cytoplasmic chromatin fragment formation during senescence
Bartlett, Bethany M.
Cell biology
Chromosomes
Gene expression
Genome integrity
Heterochromatin
Human
Inflammation
Nuclear periphery
Oncogene
Senescence
title_short TPR is required for cytoplasmic chromatin fragment formation during senescence
title_full TPR is required for cytoplasmic chromatin fragment formation during senescence
title_fullStr TPR is required for cytoplasmic chromatin fragment formation during senescence
title_full_unstemmed TPR is required for cytoplasmic chromatin fragment formation during senescence
title_sort TPR is required for cytoplasmic chromatin fragment formation during senescence
dc.creator.none.fl_str_mv Bartlett, Bethany M.
Kumar, Yatendra
Boyle, Shelagh
Chowdhury, Tamoghna
Quintanilla Cavia, Andrea
Boumendil, Charlene
Acosta Cobacho, Juan Carlos
Bickmore, Wendy A.
author Bartlett, Bethany M.
author_facet Bartlett, Bethany M.
Kumar, Yatendra
Boyle, Shelagh
Chowdhury, Tamoghna
Quintanilla Cavia, Andrea
Boumendil, Charlene
Acosta Cobacho, Juan Carlos
Bickmore, Wendy A.
author_role author
author2 Kumar, Yatendra
Boyle, Shelagh
Chowdhury, Tamoghna
Quintanilla Cavia, Andrea
Boumendil, Charlene
Acosta Cobacho, Juan Carlos
Bickmore, Wendy A.
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidad de Cantabria
dc.subject.none.fl_str_mv Cell biology
Chromosomes
Gene expression
Genome integrity
Heterochromatin
Human
Inflammation
Nuclear periphery
Oncogene
Senescence
topic Cell biology
Chromosomes
Gene expression
Genome integrity
Heterochromatin
Human
Inflammation
Nuclear periphery
Oncogene
Senescence
description During oncogene-induced senescence there are striking changes in the organisation of heterochromatin in the nucleus. This is accompanied by activation of a pro-inflammatory gene expression programme - the senescence-associated secretory phenotype (SASP) - driven by transcription factors such as NF-κB. The relationship between heterochromatin re-organisation and the SASP has been unclear. Here, we show that TPR, a protein of the nuclear pore complex basket required for heterochromatin re-organisation during senescence, is also required for the very early activation of NF-κB signalling during the stress-response phase of oncogene-induced senescence. This is prior to activation of the SASP and occurs without affecting NF-κB nuclear import. We show that TPR is required for the activation of innate immune signalling at these early stages of senescence and we link this to the formation of heterochromatin-enriched cytoplasmic chromatin fragments thought to bleb off from the nuclear periphery. We show that HMGA1 is also required for cytoplasmic chromatin fragment formation. Together these data suggest that re-organisation of heterochromatin is involved in altered structural integrity of the nuclear periphery during senescence, and that this can lead to activation of cytoplasmic nucleic acid sensing, NF-κB signalling, and activation of the SASP.
publishDate 2024
dc.date.none.fl_str_mv 2024
2024-01-01
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/10902/36499
url https://hdl.handle.net/10902/36499
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.source.none.fl_str_mv eLife, 2024, 3(13), e101702
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 15,198674

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