Endogenous DNA damage can perturb transcription, triggering a multifaceted cellular response that repairs the damage, degrades RNA polymerase II and shuts down global transcription1,2,3,4. This response is absent in the human disease Cockayne syndrome, which is caused by loss of the Cockayne syndrome A (CSA) or CSB proteins5,6,7. 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.
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All scRNA-seq data have been deposited in the Gene Expression Omnibus under accession GSE175792.
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We thank members of the K.J.P., G.P.C. and J.I.G. laboratories for critical reading of the manuscript. We thank J. Svejstrup and A. Tufegdzic Vidakovic for the pGEX-Dsk2 plasmid, E. Friedberg, G. T. van der Horst and J. Hoeijmakers for sharing the Xpc−/−, Xpa−/− and Csbm/m mice and S. Wells, M. Stewart and H. Cater for work done at MRC Harwell. We thank Pfizer for the GDF15 monoclonal antibody. K.J.P. is supported by MRC, CRUK (C42693/A23273), Wellcome Trust (106202/Z/14/Z) and European Union Research and Innovation programme Horizon 2020 (Grant Agreement Number 730879). L.M., F.A.D. and G.P.C. were supported by CRUK (C42693/A23273). J.I.G. is supported by the Hubrecht Institute. C.L.M. is supported by the Wellcome Trust (106202/Z/14/Z). M.R.C. is funded by an NIHR Research Professorship (RP-2017-08-ST2-002). J.R.F. is funded by NIHR Cambridge Blood and Transplant Research Unit Organ Donation. Z.K.T. and M.R.C. are funded by MRC HCA grant MR/S035842/1. L.G. is funded from CRUK (FC0001166), the UK Medical Research Council (FC001166) and the Wellcome Trust (FC001166). S.O. is supported by the Medical Research Council MRC.MC.UU.12012.1, a Wellcome Senior Investigator Award 214274/Z/18/Z and the NIHR Cambridge Biomedical Research Centre. J.A.T. is supported by an NIHR Clinical Lectureship (CL-2019-14-504).
The authors declare no competing interests.
Peer review information Nature thanks Stephan Herzig, Ruben van Boxtel and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Extended data figures and tables
Extended Data Fig. 1 TC-NER and formaldehyde detoxification cooperate to protect cells from formaldehyde toxicity.
a-c, Cytotoxicity of UV (a) and formaldehyde (b) in Csbm/m (a,b) or Adh5-/-Csbm/m (c) tMEF cell lines complemented with either WT or K991R CSB. Data plotted as mean and s.e.m; experiments performed in triplicate. d-e, Cytotoxicity of UV and formaldehyde in HEK293 cell lines, data shown as mean and s.e.m., experiments performed in triplicate.
Extended Data Fig. 2 Adh5-/-Csbm/m mice are born at sub-Mendelian ratios and have reduced body weight.
a, Ratios of pups from Csb+/m , Xpc+/- and Xpa+/- crosses showing that homozygous mice are born at Mendelian ratios (P calculated by two-sided Chi-squared test) b, Ratios of pups born from Adh5-/-Csb+/m, Adh5-/-Xpc+/- and Adh5-/-Xpa+/- crosses showing that both Adh5-/-Csbm/m and Adh5-/-Xpa-/- pups are born at sub-Mendelian ratios (P calculated by two-sided Chi-squared test). c, Ratios of pups born from Adh5+/- Csb+/m and Adh5-/-Csb+/m crosses showing the ratio of Adh5-/-Csbm/m pups is partially rescued when the mother is aldehyde-detoxification proficient (Adh5 +/- instead of Adh5 -/- in b, P calculated by two-sided Chi-squared test). For a, b, and c, mice were genotyped between 2-3 wk of age. d, Weights of adult male and female mice at 8 wk of age (Data shown as mean and s.e.m.; P calculated by two-sided Mann-Whitney test; n = 14, 19, 13, 12, 4, 9, 3, 7 for males left to right and 24, 30, 22, 21, 12, 9, 4, 5 for females left to right). e, Image of Csbm/m and Adh5-/-Csbm/m littermates at 12 months of age.
a, Growth curves of female mice based on weekly weights. Data shown as mean and s.e.m. n = 14, 14, 18 and 14. Along with fat mass from EchoMRI performed at 11 wk (young) and 53 wk (old). P calculated by two-sided Mann-Whitney test; data shown as mean and s.e.m.; n = 13, 14, 18, 14, 11, 13, 6 and 6 left to right. b, Bar graph of grip strength for young (3 months) and old (1 yr) mice, determined by placing all four limbs on a grid attached to a force gauge. P calculated by two-sided Mann-Whitney test, data shown as mean and s.e.m.; n = 13, 15, 18, 20, 5, 12, 12 and 8 for males left to right and 13, 14, 18, 14, 5, 3, 14 and 8 for females left to right. c, Left, age of onset plot for kyphosis. P calculated by two-sided Mantel-Cox logrank test, n = 21, 19, 22 and 9. Right, representative x-rays of Csbm/m and Adh5-/-Csbm/m mice at 1 yr of age showing kyphosis in the Adh5 -/-Csbm/m mouse. d, Brain weights of mice taken at 3 months (young) and 18 months (old). P calculated by two-tailed Student’s t-test; data shown as mean and s.e.m., n = 3 mice.
Extended Data Fig. 4 Adh5-/-Csbm/m mice succumb to chronic kidney failure and have liver abnormalities.
a, Survival and cancer-free survival curve of Adh5-/-Csbm/m and control mice. b, Bar chart indicating the cause of death for wild type, Adh5-/-, Csbm/m and Adh5 -/-Csbm/m mice (n = 18, 31, 16 and 19). c, Weights of Adh5-/-Csbm/m male and female kidneys at 12 months relative to tibia length, data shown as mean and s.e.m. (n=8, 22, 20, 16, 10, 4, 22, 17 from left to right). d, Representative H&E stained sections of kidney from Csbm/m and Adh5-/-Csbm/m mice at sequential timepoints (n=4, 3, 4, 5, from left to right). e, Bar chart of the percentage of fibrosis in the cortex of H&E stained kidney sections at sequential time points in Adh5-/-Csbm/m and terminal controls, data shown as mean and s.e.m. (n=4, 4, 4, 3, 4, 5, from left to right). f, Representative PAS stained sections of kidney showing intratubular casts from Csbm/m and Adh5-/-Csbm/m terminal mice (n=3). g, Urine obtained from indicated mice were tested for the presence of proteinuria by multistix 10SG. h, Blood counts from terminal blood samples of Adh5-/-Csbm/m and controls P calculated by two-sided Mann-Whitney test; data show as mean and s.e.m.; n = 9, 8, 6, 5 from left to right. i, Terminal serum measurements of albumin, alkaline phosphatase and alanine transaminase. P calculated by two-sided Mann-Whitney test; data show as mean and s.e.m.; n = 33, 10, 13 and 16. j, Representative H&E stained sections of liver from age-matched Csbm/m and Adh5-/-Csbm/m mice, arrows indicate cells with enlarged nuclei (n=3). k, Quantification of hepatocyte nuclear DNA content in young (3 month) and old (18 month) mice. P calculated by two-sided Student’s t-test for the content of 8n nuclei; data shown as mean and s.e.m.; n = 3 mice.
Extended Data Fig. 5 Methanol exposure exacerbates the Cockayne Syndrome phenotype in Adh5-/-Csbm/m mice.
a, Scheme outlining weekly intra-peritoneal (I.P.) injection of 1.5 g/kg methanol (or saline) and analysis of treated mice. b-c, Monthly serum levels of urea (b) and creatinine (c) from mice exposed to methanol and saline controls, data plotted as mean and s.e.m.; n = 4. d, Kidney failure-free survival curve of Adh5-/-Csbm/m mice with and without methanol exposure (P calculated by two-sided Mantel-Cox logrank test; n = 7 and 19). e, Representative image of kidneys from age-matched mice exposed to methanol or saline, taken after 24 hr of fixation. f, Representative H&E stained sections of kidney from Adh5-/-Csbm/m mice exposed to methanol or saline, G indicates glomeruli and arrows indicate atrophic tubules (n=4). g, Brain weights of age-matched mice exposed to methanol or saline. P calculated by two tailed Student’s t-test; data shown as mean and s.e.m., n = 3 mice. h, Quantification of the number of MAC2+ cells per field in mice exposed to methanol or saline. P calculated by two tailed Student’s t-test; data shown as mean and s.e.m., n = 3 mice. i, Representative immunofluorescence images of the cerebellum of Adh5-/-Csbm/m mice exposed to methanol or saline stained with MAC2 and DAPI at 40x (n=3).
Extended Data Fig. 6 Methanol reveals kidney failure in Adh5-/-Xpa-/- mice but ethanol does not in Aldh2-/-Csbm/m mice.
a, Serum measurements of albumin, alkaline phosphatase and alanine transaminase after 6 months of methanol treatment along with saline-treated controls. P calculated by two-sided Mann-Whitney test; data show as mean and s.e.m.; n = 4 mice. b, Kaplan-Meier survival curve of wild type, Adh5-/-, Xpa-/- and Adh5-/-Xpa-/- mice (n = 18, 31, 10 and 13). c, Kidney failure-free survival curve of Adh5-/-Xpa-/- mice with and without methanol exposure (P calculated by two-sided Mantel-Cox logrank test; n = 4 and 13). d, Monthly serum levels of urea and creatinine from mice exposed to methanol or saline, data plotted as mean and s.e.m.; n = 4. e, Kaplan-Meier survival curve of wild-type, Aldh2-/-, Csbm/m and Aldh2-/-Csbm/m mice (n = 18, 5, 16 and 5). f, Kaplan-Meier survival curve of wild-type, Aldh2-/-, Csbm/m and Aldh2-/-Csbm/m mice treated with 20% ethanol continuously in the drinking water (n = 6). g, Monthly serum levels of urea and creatinine from mice exposed to 20% ethanol continuously in the drinking water, data plotted as mean and s.e.m.; n = 6.
a, Scheme outlining the scRNA-seq experiment. b, UMAP plots of murine kidney scRNA-seq data for wild type, Adh5-/-, Csbm/m and Adh5-/-Csbm/m mice, n = 3 and n = 31,624, 16,023, 29,082, 29,802 cells (pDC, plasmacytoid dendritic cell; MNP, mononuclear phagocyte; LOH, loop of henle; CT, connecting tubule; DCT, distal convoluted tubules; CD-PC, collecting duct – principle cell; CD-IC, collecting duct – intercalated cell; T_NK, T cells/NK cells; B, B cells). c, Bar chart showing the composition of cell types in the scRNA-seq data. d, UMAP plot of all scRNA-seq data with each genotype labelled a different colour, arrow indicates PT cells that are distinct to Adh5-/-Csbm/m kidneys. e, UMAP plot of PT sub-clusters split by genotype. f, Heatmap indicating the top two marker genes for each PT sub-cluster (marker genes are calculated by comparing the expression of each PT sub-cluster against all remaining PTs). g, top, Feature plots of Kim-1 expression from PT sub-clusters of Adh5-/-Csbm/m cells and controls, bottom, immunofluorescence images of Adh5-/-Csbm/m and control kidney sections stained with Kim-1 taken from mice aged 12 months. h, Log2 fold change plot of DEGs from PT-4 made relative to wild-type PT-4 cells. i, top, Feature plots of Gdf15 expression from PT sub-clusters of Adh5-/-Csbm/m cells and controls, bottom, representative images of In situ hybridisation for Gdf15 mRNA (red spots) performed on Adh5-/-Csbm/m and control kidney sections, n=3.
a, Feature plots of Cyr61, Spp1 and B2m expression from PT sub-clusters of Csbm/m and Adh5-/-Csbm/m cells. b, Network of top 100 marker genes from PT sub-cluster PT-4 (marker genes were calculated by comparing expression of genes in PT-4 to all other PT cells). Data visualised in cytoscape v3.7.1 using the STRING app. Nodes are coloured based on top GO term enrichment pathway. c, Feature plots of p21, Phlda3 and Btg2 expression from PT sub-clusters of Csbm/m and Adh5-/-Csbm/m cells. d, Heatmap of expression of p53 target genes in PT cells of Adh5-/-Csbm/m and control mice.
a and b, Representative images of in situ hybridisation for Gdf15 mRNA (red spots) performed on Adh5-/-Csbm/m and control kidney sections, n=3 c, Feature plots of Gdf15 expression from LOH and CD cells for Adh5-/-Csbm/m and control mice. d, Dot plot of mean expression and fraction of cells expressing Gdf15 in the loop of henle (LOH) and collecting duct (CD) for Adh5-/-Csbm/m and control mice. e, Feature plots of Gdf15 expression from LOH and CD cells for Adh5-/-Csbm/m mice treated with methanol or untreated. f, Dot plot of mean expression and fraction of cells expressing Gdf15 in Adh5-/-Csbm/m mice treated with methanol or untreated.
a-b, Male and female mice were placed in metabolic chambers and respiratory exchange rate (R.E.R) and energy expenditure were measured over a 20-hr period, data shown as mean and s.e.m. n = 3, 5, 13 and 2 for males and n = 7, 4, 11 and 10 for females. c, male and female mice were placed in open field chambers and activity was measured over 20 min, data shown as mean and s.e.m (n=5, 10, 16 and 14 for males and n= 4, 4, 14 and 12 for females). d, Bar chart of weekly food intake from Adh5-/-Csbm/m and control mice singly housed and averaged out over 5 wk, data shown as mean and s.e.m, n=3.
Extended Data Fig. 11 GDF15 release in response to cisplatin is increased in Csbm/m mice but absent in p53-/- mice.
a, Daily weights of wild-type and Csbm/m mice exposed to weekly 0.5 mg/kg cisplatin intra-peritoneal injections alongside serum GDF15 measurements taken before and 4 wk after weekly injections. P calculated using two-sided Mann-Whitney test; data shown as mean and s.e.m.; n = 6 mice. b, Daily weights of wild-type and p53-/- mice exposed to weekly 4 mg/kg cisplatin intra-peritoneal injections alongside serum GDF15 measurements taken before and 6 wk after weekly injections. P calculated using two-sided Mann-Whitney test; data shown as mean and s.e.m.; n = 6 mice. c, In situ hybridisation for Gdf15 mRNA (red spots) performed on wild-type and p53-/- kidney sections 24 h after 4 mg/kg cisplatin treatment (n=3).
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Mulderrig, L., Garaycoechea, J.I., Tuong, Z.K. et al. Aldehyde-driven transcriptional stress triggers an anorexic DNA damage response. Nature 600, 158–163 (2021). https://doi.org/10.1038/s41586-021-04133-7
Nature Reviews Nephrology (2022)