Aldehyde-driven transcriptional stress triggers an anorexic DNA damage response.

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.

• Authors: 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 Crossan, Menna R Clatworthy, Ketan J Patel
• Journal: Nature (Nature) Vol. 600 Issue 7887 Pg. 158-163 (12 2021) ISSN: 1476-4687 [Electronic] England
• PMID: 34819667 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• Gdf15 protein, mouse
• Growth Differentiation Factor 15
• Poly-ADP-Ribose Binding Proteins
• Formaldehyde
• Adh5 protein, mouse
• Alcohol Dehydrogenase
• Ercc6 protein, mouse
• DNA Repair Enzymes

Topics

• Alcohol Dehydrogenase (deficiency, metabolism)
• Animals
• Brain (drug effects, metabolism, pathology)
• Cachexia (complications)
• Cockayne Syndrome (chemically induced, complications, genetics, pathology)
• DNA Damage
• DNA Repair Enzymes (deficiency)
• Disease Models, Animal
• Female
• Formaldehyde (adverse effects, metabolism)
• Growth Differentiation Factor 15 (antagonists & inhibitors, biosynthesis, genetics)
• Kidney Tubules, Proximal (drug effects, metabolism, pathology)
• Male
• Mice
• Poly-ADP-Ribose Binding Proteins (deficiency)
• Renal Insufficiency (complications)
• Stress, Physiological (drug effects)
• Transcription, Genetic (drug effects, genetics)