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Aldehyde-driven transcriptional stress triggers an anorexic DNA damage response

Author

Listed:
  • Lee Mulderrig

    (University of Oxford, John Radcliffe Hospital
    MRC Laboratory of Molecular Biology)

  • Juan I. Garaycoechea

    (Hubrecht Institute)

  • Zewen K. Tuong

    (University of Cambridge
    Wellcome Genome Campus)

  • Christopher L. Millington

    (University of Oxford, John Radcliffe Hospital)

  • Felix A. Dingler

    (University of Oxford, John Radcliffe Hospital)

  • John R. Ferdinand

    (University of Cambridge)

  • Liam Gaul

    (The Francis Crick Institute)

  • John A. Tadross

    (University of Cambridge
    University of Cambridge)

  • Mark J. Arends

    (University of Edinburgh, Cancer Research UK Edinburgh Centre, IGMM)

  • Stephen O’Rahilly

    (University of Cambridge)

  • Gerry P. Crossan

    (MRC Laboratory of Molecular Biology)

  • Menna R. Clatworthy

    (University of Cambridge
    Wellcome Genome Campus
    University of Cambridge and NIHR Cambridge Biomedical Research Centre)

  • Ketan J. Patel

    (University of Oxford, John Radcliffe Hospital
    MRC Laboratory of Molecular Biology)

Abstract

Endogenous DNA damage can perturb transcription, triggering a multifaceted cellular response that repairs the damage, degrades RNA polymerase II and shuts down global transcription1–4. This response is absent in the human disease Cockayne syndrome, which is caused by loss of the Cockayne syndrome A (CSA) or CSB proteins5–7. However, the source of endogenous DNA damage and how this leads to the prominent degenerative features of this disease remain unknown. Here we find that endogenous formaldehyde impedes transcription, with marked physiological consequences. Mice deficient in formaldehyde clearance (Adh5−/−) and CSB (Csbm/m; Csb is also known as Ercc6) develop cachexia and neurodegeneration, and succumb to kidney failure, features that resemble human Cockayne syndrome. Using single-cell RNA sequencing, we find that formaldehyde-driven transcriptional stress stimulates the expression of the anorexiogenic peptide GDF15 by a subset of kidney proximal tubule cells. Blocking this response with an anti-GDF15 antibody alleviates cachexia in Adh5−/−Csbm/m mice. Therefore, CSB provides protection to the kidney and brain against DNA damage caused by endogenous formaldehyde, while also suppressing an anorexic endocrine signal. The activation of this signal might contribute to the cachexia observed in Cockayne syndrome as well as chemotherapy-induced anorectic weight loss. A plausible evolutionary purpose for such a response is to ensure aversion to genotoxins in food.

Suggested Citation

  • Lee Mulderrig & Juan I. Garaycoechea & Zewen K. Tuong & Christopher L. Millington & Felix A. Dingler & John R. Ferdinand & Liam Gaul & John A. Tadross & Mark J. Arends & Stephen O’Rahilly & Gerry P. C, 2021. "Aldehyde-driven transcriptional stress triggers an anorexic DNA damage response," Nature, Nature, vol. 600(7887), pages 158-163, December.
  • Handle: RePEc:nat:nature:v:600:y:2021:i:7887:d:10.1038_s41586-021-04133-7
    DOI: 10.1038/s41586-021-04133-7
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    Cited by:

    1. Diana A. Llerena Schiffmacher & Shun-Hsiao Lee & Katarzyna W. Kliza & Arjan F. Theil & Masaki Akita & Angela Helfricht & Karel Bezstarosti & Camila Gonzalo-Hansen & Haico Attikum & Matty Verlaan-de Vr, 2024. "The small CRL4CSA ubiquitin ligase component DDA1 regulates transcription-coupled repair dynamics," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Yongchang Zhu & Xiping Zhang & Meng Gao & Yanchao Huang & Yuanqing Tan & Avital Parnas & Sizhong Wu & Delin Zhan & Sheera Adar & Jinchuan Hu, 2024. "Coordination of transcription-coupled repair and repair-independent release of lesion-stalled RNA polymerase II," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Ondrej Suchanek & John R. Ferdinand & Zewen K. Tuong & Sathi Wijeyesinghe & Anita Chandra & Ann-Katrin Clauder & Larissa N. Almeida & Simon Clare & Katherine Harcourt & Christopher J. Ward & Rachael B, 2023. "Tissue-resident B cells orchestrate macrophage polarisation and function," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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