Mammals divert endogenous genotoxic formaldehyde into one-carbon metabolism

Guillermo Burgos-Barragan, Niek Wit, Johannes Meiser, Felix A. Dingler, Matthias Pietzke, Lee Mulderrig, Lucas B. Pontel, Ivan V. Rosado, Thomas F. Brewer, Rebecca L. Cordell, Paul S. Monks, Christopher J. Chang, Alexei Vazquez and Ketan J. Patel ()
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Guillermo Burgos-Barragan: MRC Laboratory of Molecular Biology
Niek Wit: MRC Laboratory of Molecular Biology
Johannes Meiser: Cancer Research UK Beatson Institute
Felix A. Dingler: MRC Laboratory of Molecular Biology
Matthias Pietzke: Cancer Research UK Beatson Institute
Lee Mulderrig: MRC Laboratory of Molecular Biology
Lucas B. Pontel: MRC Laboratory of Molecular Biology
Ivan V. Rosado: Instituto de Biomedicina de Sevilla (IBiS) Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla
Thomas F. Brewer: and Howard Hughes Medical Institute, University of California, Berkeley
Rebecca L. Cordell: University of Leicester
Paul S. Monks: University of Leicester
Christopher J. Chang: and Howard Hughes Medical Institute, University of California, Berkeley
Alexei Vazquez: Cancer Research UK Beatson Institute
Ketan J. Patel: MRC Laboratory of Molecular Biology

Nature, 2017, vol. 548, issue 7669, 549-554

Abstract: 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.

Date: 2017
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DOI: 10.1038/nature23481

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