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Mammals divert endogenous genotoxic formaldehyde into one-carbon metabolism
Open accessAbstract
The folate-driven one-carbon (1C) cycle is a fundamental metabolic hub in cells that enables the synthesis of nucleotides and amino acids and epigenetic modifications. This cycle might also release formaldehyde, a potent protein and DNA crosslinking agent that organisms produce in substantial quantities. Here we show that supplementation with tetrahydrofolate, the essential cofactor of this cycle, and other oxidation-prone folate derivatives kills human, mouse and chicken cells that cannot detoxify formaldehyde or that lack DNA crosslink repair. Notably, formaldehyde is generated from oxidative decomposition of the folate backbone. Furthermore, we find that formaldehyde detoxification in human cells generates formate, and thereby promotes nucleotide synthesis. This supply of 1C units is sufficient to sustain the growth of cells that are unable to use serine, which is the predominant source of 1C units. These findings identify an unexpected source of formaldehyde and, more generally, indicate that the detoxification of this ubiquitous endogenous genotoxin creates a benign 1C unit that can sustain essential metabolism.
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“Notably, two mito-1C metabolism genes, SHMT2 and MTHFD1L, and the S-formylglutathione hydrolase gene, ESD, involved in GSH-mediated formaldehyde detoxification (12) were identified in the CRISPRko screen.”
From Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction (2022) · cites this paper as [12]
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Metadata
- Authors
- Burgos-Barragan, G., Wit, N., Meiser, J., Dingler, F. A., Pietzke, M., Mulderrig, L., Pontel, L. B., Rosado, I. V., Brewer, T. F., Cordell, R. L., Monks, P. S., Chang, C. J., Vazquez, A., & Patel, K. J.
- Affiliations
- MRC Laboratory of Molecular Biology (GB)
- Cancer Research UK Scotland Institute (GB)
- Howard Hughes Medical Institute (US)
- University of Leicester (GB)
- Corresponding author
- Patel, Ketan J.
- ORCID
- Venue
- Nature
- Published
- 2017-08-16
- Volume
- 548
- Issue
- 7669
- Pages
- 549-554
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5714256
- OpenAlex
- W2748677962
- Cited by
- 359
- References
- 36
- Citations by year
- 2026: 29 · 2025: 48 · 2024: 50 · 2023: 38 · 2022: 42 · 2021: 40 · 2020: 44 · 2019: 42 · 2018: 24 · 2017: 2
- FWCI
- 26.78
- Type
- journal article
- Language
- en
- Update notices
- erratum (2017-08-23)
- Open access
- bronze
- doi.org
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RISalud Institutional Health Repository of Andalucía (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- CONICET Digital (CONICET) (submittedVersion, cc-by-nc-sa)
- Funders
- Wellcome Trust (106202, 106202/Z/14/Z)
- Cancer Research UK (23273, A18076, A21140, C596/A21140, A13647, 21140)
- European Commission
- Deutsche Forschungsgemeinschaft (ME 4636/2-1)
- National Institutes of Health (79465)
- Medical Research Council
- Engineering and Physical Sciences Research Council
- National Institute of General Medical Sciences (T32GM066698, R01GM079465)
- National Institute of Environmental Health Sciences (P42ES004705, R01ES028096)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Folate and B Vitamins Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- formaldehyde detoxification, one-carbon metabolism, folic acid, tetrahydrofolate, ADH5, alcohol dehydrogenase, formate, nucleotide synthesis, DNA cross-linking, genotoxicity, cancer therapy
- MeSH terms
- Alcohol Dehydrogenase, Animals, Carbon, Cell Line, Chickens, Coenzymes, Cross-Linking Reagents, DNA Damage, DNA Repair, Folic Acid, Formaldehyde, Humans, Inactivation, Metabolic, Mutagens, Nucleotides, Oxidation-Reduction, Serine, Tetrahydrofolates, Mice, Metabolic Networks and Pathways
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