@article{10902/36499,
year = {2024},
url = {https://hdl.handle.net/10902/36499},
abstract = {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.},
organization = {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).},
publisher = {eLife, 2024, 3(13), e101702},
title = {TPR is required for cytoplasmic chromatin fragment formation during senescence},
author = {Bartlett, Bethany M. and Kumar, Yatendra and Boyle, Shelagh and Chowdhury, Tamoghna and Quintanilla Cavia, Andrea and Boumendil, Charlene and Acosta Cobacho, Juan Carlos and Bickmore, Wendy A.},
}