Aldehyde-driven transcriptional stress triggers an anorexic DNA damage response

Abstract

The genome is subjected to many forms of attack that can compromise its stability. Such forms of attack can emerge from endogenous or exogenous sources and must be counteracted by specialised repair pathways. Indeed, the absence of these pathways results in catastrophic human diseases. The biochemical steps and proteins involved with removal of damaged DNA from the genome are well characterised. However, the source of DNA damage for which these pathways have evolved to counteract remains unclear in many instances. Many of these pathways are also compensatory and have complex relationships with each other, therefore, attributing specific repair functions to them is not always straightforward.

This work genetically dissects the function the key DNA repair nuclease, XPF-ERCC1. This nuclease operates in the Fanconi Anaemia (FA) pathway and Nucleotide excision repair (NER). Unexpectedly, ablation of these two DNA repair pathways does not result in equivalent cellular or mouse phenotypes. However, these two pathways do appear to play independent roles in the cellular protection against the endogenous toxic metabolite, formaldehyde.

We find that endogenous formaldehyde impedes transcription, requiring repair via Cockayne Syndrome B (CSB). Mice deficient in formaldehyde clearance (Adh5-/-) and CSB (Csbm/m) develop cachexia, neurodegeneration and succumb to kidney failure, akin to human Cockayne Syndrome (CS). Furthermore, using scRNA-seq we reveal that formaldehyde-driven transcriptional stress stimulates the expression of the anorexiogenic peptide GDF15 by a subset of kidney proximal tubule (PT) cells. Blocking this response with a 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, whilst also suppressing an anorexic endocrine signal. The activation of this signal might contribute to the cachexia observed in CS as well chemotherapy-induced anorectic weight loss. A plausible evolutionary purpose for such a response is to ensure aversion to genotoxins in food.