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Updated: Oct 12, 2025

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Aldehyde-driven transcriptional stress triggers an anorexic DNA damage response

Lee Mulderrig1,2, Juan I Garaycoechea3, Zewen K Tuong4,5

  • 1MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.

Nature
|November 25, 2021
PubMed

Insights

Endogenous formaldehyde causes DNA damage, impeding transcription and leading to Cockayne syndrome-like symptoms. Blocking the GDF15 signal alleviates cachexia, suggesting a role in disease pathogenesis.

Area of Science:

  • Molecular Biology
  • Genetics
  • Toxicology

Background:

  • Endogenous DNA damage disrupts cellular processes like transcription.
  • Cockayne syndrome, a human disease, lacks this DNA damage response due to mutations in CSA or CSB proteins.
  • The source of endogenous DNA damage and its link to Cockayne syndrome's degenerative features are unknown.

Purpose of the Study:

  • To identify the source of endogenous DNA damage.
  • To investigate the physiological consequences of this damage.
  • To understand the role of CSB protein in protecting against formaldehyde-induced DNA damage and associated symptoms.

Main Methods:

  • Utilized mouse models deficient in formaldehyde clearance (Adh5-/-) and CSB (Csb(m/m)).
  • Employed single-cell RNA sequencing to analyze gene expression changes.
  • Administered anti-GDF15 antibody treatment to assess therapeutic effects.

Main Results:

  • Mice lacking formaldehyde clearance and CSB exhibited cachexia, neurodegeneration, and kidney failure, mimicking Cockayne syndrome.
  • Formaldehyde-induced transcriptional stress upregulated the anorexiogenic peptide GDF15 in kidney proximal tubule cells.
  • Anti-GDF15 antibody treatment ameliorated cachexia in the studied mice.

Conclusions:

  • CSB protein protects against DNA damage from endogenous formaldehyde in the kidney and brain.
  • The upregulation of GDF15 contributes to cachexia in Cockayne syndrome and potentially chemotherapy-induced weight loss.
  • This cellular response may have evolved to promote aversion to genotoxins in food.

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