Mammals divert endogenous genotoxic formaldehyde into one-carbon metabolism

Burgos-Barragan, G. et al. (2017) Mammals divert endogenous genotoxic formaldehyde into one-carbon metabolism. Nature, 548(7669), pp. 549-554. (doi:10.1038/nature23481) (PMID:28813411) (PMCID:PMC5714256)

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Abstract

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.

Item Type:Articles
Additional Information:F.A.D. and L.M. were funded by CRUK. I.V.R. was funded by BFU2013-42918-P, AES15/01409 (CP12/03273), European Union (FEDER) and RYC-2015-18670. We thank the NIH (GM 79465 to C.J.C.) for support of this work. C.J.C. is an Investigator of the Howard Hughes Medical Institute. T.F.B. was partially supported by a Chemical Biology Training Grant from the NIH (T32 GM066698). R.L.C. and P.S.M. are supported by the MRC. R.L.C. is also supported by the EPSRC. J.M., M.P. and A.V. were funded by CRUK (C596/A21140 and C596/A18076). J.M. was also funded by a DFG Fellowship (ME 4636/2-1).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Vazquez, Alexei
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., and Patel, K. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Nature
Publisher:Nature Research
ISSN:0028-0836
ISSN (Online):1476-4687
Published Online:16 August 2017

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