Mammals divert endogenous genotoxic formaldehyde into one-carbon metabolism

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.

Mitochondrial One-Carbon Pathway Supports Cytosolic Folate Integrity in Cancer Cells

“…The folate degradation product identified in the present study, pAcABG n , may act as a competitive inhibitor for folate enzymes. Folate decomposition is known to produce formaldehyde that can result in DNA damage (Burgos-Barragan et al, 2017), and it remains to be determined quantitatively how significant this source of formaldehyde is. Exploring these open questions and devising strategies to further enhance the degree of cellular folate depletion may provide insights into more effective use of methotrexate as a single agent or in combination with other drugs.…”

Control of Ribosomal RNA Transcription by Nutrients

“…This biochemical route provides a cell with formaldehyde detoxification as well as utilizable one-carbon units, which contribute to nucleotide synthesis. Therefore, cells reserve materials for one-carbon metabolism as methyl marks [100], which are released by KDM2A on starvation. These two examples of acetylation and methylation suggest that modifications of the epigenetic marks are not only controlled by intracellular energy conditions, but also function as reservoirs in chromatin for biological resources.…”

Chemiluminescent Probes for Activity‐Based Sensing of Formaldehyde Released from Folate Degradation in Living Mice

“…Indeed, recent progress in developing fluorescent probes for FA detection in cells has elucidated more sophisticated biological roles for FA as both an exogenous toxin and an endogenous signaling molecule. Included is the discovery that FA is endogenously produced in the folate cycle through specific intermediates like tetrahydrofolate (THF) and 5,10-methyleneTHF, but not others like 5-methylTHF, [8] opening new doors to investigate the intriguing yet complex relationships between FA, methylation status and carcinogenesis. Despite these advances in fluorescent FA detection, FA imaging in living mammals is limited to an aza-Cope-based PET tracer, [33] which requires specialized equipment to implement.…”

“…We observed an immediate difference at the first imaging point between the tetrahydrofolate- and vehicle-treated mice, which is consistent with the rapid rate of tetrahydrofolate metabolism detailed recently in cell models. [8] …”