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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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Cites
Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity
Ran, F. A., Hsu, P. D., Lin, C.-Y., Gootenberg, J. S., Konermann, S., Trevino, A. E., Scott, D. A., Inoue, A., Matoba, S., Zhang, Y., et al. (2013) · Cell · doi:10.1016/j.cell.2013.08.021 · Cited by 3,299
One-Carbon Metabolism in Health and Disease
Ducker, G. S., & Rabinowitz, J. D. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2016.08.009 · Cited by 2,239
Farber, S., Diamond, L. K., Mercer, R. D., Sylvester, R. F., & Wolff, J. A. (1948) · New England Journal of Medicine · doi:10.1056/nejm194806032382301 · Cited by 1,806
Compartmentalization of Mammalian Folate-Mediated One-Carbon Metabolism
Tibbetts, A. S., & Appling, D. R. (2010) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.012809.104810 · Cited by 692
Reversal of cytosolic one-carbon flux compensates for loss of the mitochondrial folate pathway
Ducker, G. S., Chen, L., Morscher, R. J., Ghergurovich, J. M., Esposito, M., Teng, X., Kang, Y., & Rabinowitz, J. D. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.04.016 · Cited by 419
Endogenous Formaldehyde Is a Hematopoietic Stem Cell Genotoxin and Metabolic Carcinogen
Pontel, L. B., Rosado, I. V., Burgos-Barragan, G., Garaycoechea, J. I., Yu, R., Arends, M. J., Chandrasekaran, G., Broecker, V., Wei, W., Liu, L., et al. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.08.020 · Cited by 397
Self-citationGenotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function
Garaycoechea, J. I., Crossan, G. P., Langevin, F., Daly, M. G., Arends, M. J., & Patel, K. J. (2012) · Nature · doi:10.1038/nature11368 · Cited by 390
Self-citationAn Aza-Cope Reactivity-Based Fluorescent Probe for Imaging Formaldehyde in Living Cells
Brewer, T. F., & Chang, C. J. (2015) · Journal of the American Chemical Society · doi:10.1021/jacs.5b05340 · Cited by 272
Self-citationHeck, H. D., Casanova, M., DODD, P. B., Schachter, E. N., Witek, T. J., & Tosun, T. (1985) · American Industrial Hygiene Association Journal · doi:10.1080/15298668591394275 · Cited by 248
Formaldehyde Dehydrogenase from Human Liver
Uotila, L., & Koivusalo, M. (1974) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)81287-5 · Cited by 216
Mutant loxP vectors for selectable marker recycle and conditional knock-outs
Arakawa, H., Lodygin, D., & Buerstedde, J.-M. (2001) · BMC Biotechnology · doi:10.1186/1472-6750-1-7 · Cited by 199
Mechanisms of human histone and nucleic acid demethylases
Walport, L. J., Hopkinson, R. J., & Schofield, C. J. (2012) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2012.09.015 · Cited by 194
Formaldehyde catabolism is essential in cells deficient for the Fanconi anemia DNA-repair pathway
Rosado, I. V., Langevin, F., Crossan, G. P., Takata, M., & Patel, K. J. (2011) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2173 · Cited by 184
Self-citationSerine one-carbon catabolism with formate overflow
Meiser, J., Tumanov, S., Maddocks, O., Labuschagne, C. F., Athineos, D., Van Den Broek, N., Mackay, G. M., Gottlieb, E., Blyth, K., Vousden, K., et al. (2016) · Science Advances · doi:10.1126/sciadv.1601273 · Cited by 174
Self-citationLuo, W., Li, H., Zhang, Y., & ANG, C. Y. W. (2001) · Journal of Chromatography B Biomedical Sciences and Applications · doi:10.1016/s0378-4347(00)00552-1 · Cited by 149
Bruemmer, K. J., Walvoord, R. R., Brewer, T. F., Burgos-Barragan, G., Wit, N., Pontel, L. B., Patel, K. J., & Chang, C. J. (2017) · Journal of the American Chemical Society · doi:10.1021/jacs.6b12460 · Cited by 142
Self-citationThe Structure of “Active Formaldehyde” (N5, N10 -Methylene Tetrahydrofolic Acid)1
Osborn, M., Talbert, P. T., & Huennekens, F. M. (1960) · Journal of the American Chemical Society · doi:10.1021/ja01503a043 · Cited by 120
Brouwer, V. D., Zhang, G., Storozhenko, S., Straeten, D. V. D., & Lambert, W. E. (2007) · Phytochemical Analysis · doi:10.1002/pca.1006 · Cited by 115
High intake of folic acid disrupts embryonic development in mice
Pickell, L., Brown, K., Li, D., Wang, X., Deng, L.-Y., Wu, Q. H., Selhub, J., Luo, L., Jerome‐Majewska, L. A., & Rozen, R. R. (2010) · Birth Defects Research Part A Clinical and Molecular Teratology · doi:10.1002/bdra.20754 · Cited by 111
Purification and Properties of S-Formylglutathione Hydrolase from Human Liver
Uotila, L., & Koivusalo, M. (1974) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)81288-7 · Cited by 100
Folic acid supplementation can adversely affect murine neural tube closure and embryonic survival
Marean, A., Graf, A. E., Zhang, Y., & Niswander, L. A. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr289 · Cited by 89
McCarthy, E. A., Titus, S. A., Taylor, S. M., Jackson‐Cook, C. K., & Moran, R. G. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m403677200 · Cited by 68
Patel, H., Pietro, E. D., & MacKenzie, R. E. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m301718200 · Cited by 62
Oxidative degradation of dihydrofolate and tetrahydrofolate
Chippel, D., & Scrimgeour, K. G. (1970) · Canadian Journal of Biochemistry · doi:10.1139/o70-156 · Cited by 55
Impact of dietary folic acid on reduced folates in mouse plasma and tissues
Schmitz, J. C., Grlndey, G. B., Schultz, R. M., & Priest, D. G. (1994) · Biochemical Pharmacology · doi:10.1016/0006-2952(94)90103-1 · Cited by 50
Wit, N., Buoninfante, O. A., van den Berk, P. C. M., Jansen, J. G., Hogenbirk, M. A., de Wind, N., & Jacobs, H. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku1301 · Cited by 49
Self-citationChen, Z., Rozen, R. R., Ghandour, H., & Selhub, J. (2004) · Journal of Nutrition · doi:10.1093/jn/134.11.2975 · Cited by 49
Atmospheric pressure chemical ionization mass spectrometry of aldehydes in biological matrices
Nagy, K., Pollreisz, F., Takáts, Z., & Vékey, K. (2004) · Rapid Communications in Mass Spectrometry · doi:10.1002/rcm.1648 · Cited by 48
Lawrence, S. A., Titus, S. A., Ferguson, J., Heineman, A., Taylor, S. M., & Moran, R. G. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.593244 · Cited by 40
Urinary Excretion of Deuterium-Labeled Folate and the Metabolite p-Aminobenzoylglutamate in Humans
Kownacki-Brown, P. A., Wang, C., Bailey, L. B., Toth, J. P., & Gregory, J. F. (1993) · Journal of Nutrition · doi:10.1093/jn/123.6.1101 · Cited by 32
Human Mus81 and FANCB independently contribute to repair of DNA damage during replication
Nomura, Y., Adachi, N., & Koyama, H. (2007) · Genes to Cells · doi:10.1111/j.1365-2443.2007.01124.x · Cited by 28
Witham, K. L., Butcher, N. J., Sugamori, K. S., Brenneman, D., Grant, D. M., & Minchin, R. F. (2013) · PLoS ONE · doi:10.1371/journal.pone.0077923 · Cited by 22
Murphy, M., & Scott, J. M. (1979) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/0304-4165(79)90071-0 · Cited by 22
The fate of [3H]folic acid in folate-adequate rats
Scott, K. C., & Gregory, J. F. (1996) · The Journal of Nutritional Biochemistry · doi:10.1016/0955-2863(96)00026-5 · Cited by 17
Horne, D. W. (2003) · Journal of Nutrition · doi:10.1093/jn/133.2.476 · Cited by 15
Alcohol Dehydrogenase 5 Is a Source of Formate for De Novo Purine Biosynthesis in HepG2 Cells
Bae, S., Chon, J., Field, M. S., & Stover, P. J. (2017) · Journal of Nutrition · doi:10.3945/jn.116.244467 · Cited by 14
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Bruemmer, K. J., Crossley, S. W. M., & Chang, C. J. (2019) · Angewandte Chemie International Edition · doi:10.1002/anie.201909690 · Cited by 270
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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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