Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Correspondence
  • Published:

Age-associated transcriptional stress due to accelerated elongation and increased stalling of RNAPII

Nature Genetics volume 55, pages 2011–2012 (2023)Cite this article

Subjects

Two recent studies, coauthored by us, reported age-associated increase in transcriptional stress due to elevated stalling of RNA polymerases and accelerated transcription elongation. These findings may seem to contradict each other at first sight. Here we argue why this is not the case.

Transcription is an essential process for cellular homeostasis, continuously fueling gene expression cycles over the course of a cell’s lifetime. Several recent publications have brought to light how increased transcriptional stress — affecting initiation1, elongation2,3 and termination4 — contributes to the age-associated loss of cellular and organismal homeostasis. Gyenis et al.2 showed that the number of transcribing RNA polymerase II (RNAPII) holoenzymes increases with age in murine liver, despite a decline in nascent RNA production. They ascribed this apparent contradiction to an increase in the number of ‘stalled’ RNAPs, which can affect up to 40% of all elongating RNAPII in the liver. This is likely to be due to the age-associated accumulation of stochastic DNA damage, physically blocking transcriptional elongation. RNAPII stalling is preferentially detected in long genes, as the probability of encountering a DNA lesion is proportional to gene length, thereby leading to a reduced and imbalanced transcriptional output.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Schematics of the effects of RNAPII kinetics on intronic read distributions.

References

  1. Sen, P. et al. Nat. Aging 3, 402–417 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Gyenis, A. et al. Nat. Genet. 55, 268–279 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Debès, C. et al. Nature 616, 814–821 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Chen, M. et al. Genome Res. 28, 285–294 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wada, Y. et al. Proc. Natl Acad. Sci. USA 106, 18357–18361 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bochkis, I. M., Przybylski, D., Chen, J. & Regev, A. Cell Rep. 9, 996–1006 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bozukova, M. et al. Mol. Syst. Biol. 18, e11002 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Muniz, L., Nicolas, E. & Trouche, D. EMBO J. 40, e105740 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Fritsch, C. et al. Proc. Natl Acad. Sci. USA 118, e2004077118 (2021).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

A.G., J.P. and J.H.J.H. were supported by the European Research Council Advanced Grant Dam2Age, ONCODE (Dutch Cancer Society), the US National Institutes of Health (grant PO1 AG017242), Memorabel (ZonMW), the BBoL (NWO-ENW), the Deutsche Forschungsgemeinschaft (FOR 5504 project 496650118), EJP-RD project TC-NER RD20-113 and the Olav Thon Stiffelsen International Award to J.H.J.H. (2017). A.P. was supported by the Deutsche Forschungsgemeinschaft (SFB1565 project INST186/1479-1). A.P. and A.B. were supported by the Deutsche Forschungsgemeinschaft, Germany’s Excellence Strategy–CECAD, EXC 2030–390661388.

Author information

Authors and Affiliations

  1. Cluster of Excellence on Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, Cologne, Germany

    Antonios Papadakis & Andreas Beyer

  2. Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands

    Akos Gyenis, Joris Pothof & Jan H. J. Hoeijmakers

  3. University of Cologne, Faculty of Medicine, Cluster of Excellence on Cellular Stress Responses in Aging-associated Diseases (CECAD), Institute for Genome Stability in Ageing and Disease, Cologne, Germany

    Akos Gyenis & Jan H. J. Hoeijmakers

  4. Princess Maxima Center for Pediatric Oncology, Oncode Institute, Utrecht, The Netherlands

    Jan H. J. Hoeijmakers

  5. Institute of Pathology, University Medical Centre Göttingen, Göttingen, Germany

    Argyris Papantonis

  6. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany

    Andreas Beyer

  7. Institute for Genetics, Faculty of Mathematics and Natural Sciences, University of Cologne, Cologne, Germany

    Andreas Beyer

Authors
  1. Antonios Papadakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Akos Gyenis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joris Pothof
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jan H. J. Hoeijmakers
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Argyris Papantonis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andreas Beyer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andreas Beyer.

Ethics declarations

Competing interests

The authors declare no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Papadakis, A., Gyenis, A., Pothof, J. et al. Age-associated transcriptional stress due to accelerated elongation and increased stalling of RNAPII. Nat Genet 55, 2011–2012 (2023). https://doi.org/10.1038/s41588-023-01601-w

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41588-023-01601-w

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing