TPR is required for cytoplasmic chromatin fragment formation during senescence

  1. Bethany M Bartlett
  2. Yatendra Kumar
  3. Shelagh Bolyle
  4. Tamoghna Chowdhury
  5. Andrea Quintanilla
  6. Charlene Boumendil
  7. Juan Carlos Acosta  Is a corresponding author
  8. Wendy A Bickmore  Is a corresponding author
  1. University of Edinburgh, United Kingdom
  2. Institute of Biomedicine and Biotechnology of Cantabria, Spain
  3. Université de Montpellier, France

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
The following previously published data sets were used

Article and author information

Author details

  1. Bethany M Bartlett

    Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1999-7675
  2. Yatendra Kumar

    Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Shelagh Bolyle

    Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Tamoghna Chowdhury

    Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0009-0004-6287-7227
  5. Andrea Quintanilla

    Institute of Biomedicine and Biotechnology of Cantabria, Santander, Spain
    Competing interests
    The authors declare that no competing interests exist.
  6. Charlene Boumendil

    Institute of Human Genetics, Université de Montpellier, Montpellier, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1953-3902
  7. 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7989-7329
  8. 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.
    ORCID icon "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

© 2024, Bartlett et al.

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.

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  1. Bethany M Bartlett
  2. Yatendra Kumar
  3. Shelagh Bolyle
  4. Tamoghna Chowdhury
  5. Andrea Quintanilla
  6. Charlene Boumendil
  7. Juan Carlos Acosta
  8. Wendy A Bickmore
(2024)
TPR is required for cytoplasmic chromatin fragment formation during senescence
eLife 13:e101702.
https://doi.org/10.7554/eLife.101702

Share this article

https://doi.org/10.7554/eLife.101702

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