TPR is required for cytoplasmic chromatin fragment formation during senescence

Abstract
Data availability
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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.

Data availability

The RNA-seq and ATAC-seq data generated in this study have been deposited in NCBI GEO, but the data are currently private. Access tokens for reviewers to access these submission data are:RNA seqhttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE264387Access token: qzihsgiwhlqvzopATAC seqhttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE264390Access token: irstugcgzfqrlib

The following data sets were generated

1. Bickmore WA
2. et al
(2024) TPR is required for cytoplasmic chromatin fragment formation during senescence
NCBI Gene Expression Omnibus, GSE264387.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE264387
1. Bickmore WA
2. et al
(2024) TPR is required for cytoplasmic chromatin fragment formation during senescence
NCBI Gene Expression Omnibus, GSE264390.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE264390

The following previously published data sets were used

1. Parry et al
(2018) H3K27ac ChIP-seq
NCBI Gene Expression Omnibus, GSE103590.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE103590

Article and author information

Author details

Bethany M Bartlett

Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-1999-7675
Yatendra Kumar

Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Shelagh Bolyle

Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Tamoghna Chowdhury

Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, United Kingdom

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0009-0004-6287-7227
Andrea Quintanilla

Institute of Biomedicine and Biotechnology of Cantabria, Santander, Spain

Competing interests
The authors declare that no competing interests exist.
Charlene Boumendil

Institute of Human Genetics, Université de Montpellier, Montpellier, France

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1953-3902
Juan Carlos Acosta

Institute of Biomedicine and Biotechnology of Cantabria, Santander, Spain

For correspondence
juan.acosta@unican.es

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-7989-7329
Wendy A Bickmore

Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom

For correspondence
wendy.bickmore@ed.ac.uk

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-6660-7735

Funding

Medical Research Council (MC_UU_00007/2)

Wendy A Bickmore

Medical Research Council (MC_UU_00035/7)

Wendy A Bickmore

Wellcome Trust (217120/Z/19/Z)

Yatendra Kumar
Wendy A Bickmore

Cancer Research UK (C47559/A16243)

Juan Carlos Acosta

Ministry of Science and Innovation, Government of Spain (Proyecto PID2020-117860GB-I00)

Juan Carlos Acosta

Agence Nationale de la Recherche (ANR-21-CE12-0039)

Charlene Boumendil

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.