Folate and formaldehyde: from vitamin to genotoxin to DNA building block

The genotoxic effect and metabolic role of folate and formaldehyde
The two faces of folate and formaldehyde. On one hand, tetrahydrofolate (THF), the active form of folate, decomposes to release formaldehyde which damages DNA. On the other hand, formaldehyde detoxification by ADH5 converts this genotoxin into a benign one-carbon (1C) unit which is carried by THF and used for the synthesis of nucleotides.

Cell growth requires the synthesis of molecules, such as nucleotides to make DNA and amino acids to make proteins. One essential building block of these is the one carbon unit. This is produced by the one carbon (1C) cycle, which requires the vitamin folate and the amino acid serine (the main source of the 1C unit). 1C metabolism is important for human health, and folate deficiency causes birth defects, nerve damage and anaemia. However, recent research by KJ Patel’s group in the LMB’s PNAC Division, in collaboration with Alexei Vazquez at the CRUK Beatson Institute in Glasgow and Chris Chang from the University of Berkeley, has shown that folate is also a source of formaldehyde – the well-known preservative and toxin – which if left unchecked damages DNA. Conversely, detoxification of formaldehyde can result in the production of essential molecules needed for cell growth. Thus, folate and formaldehyde have two faces: a beneficial side because they provide some of the chemical building blocks for cells to live and grow, and a dangerous side because they damage DNA.

Previous work from KJ Patel’s lab had shown that mammals are continuously producing the toxin formaldehyde. They further showed that when the protection against this molecule is removed in mice then the levels of endogenous formaldehyde rise leading to overwhelming DNA damage and rapid death. Our cells possess two tiers of protection against this endogenously produced formaldehyde: the first tier consists of an enzyme called alcohol dehydrogenase 5 (ADH5) that detoxifies it, the second tier or essential backup is DNA repair which fixes the damage done to chromosomes by formaldehyde. In this most recent work the scientists uncover where and how in our bodies some of this formaldehyde comes from. They further show that as the cell processes formaldehyde using tier 1 protection, it essentially converts this violent reactive chemical into a molecule that is eventually used to make DNA.

Guillermo Burgos Barragan and Niek Wit from KJ’s group, assisted by Alexie Vasquez’s lab, used a combination of genetics, biochemistry and metabolic analysis to show that tetrahydrofolate (THF), the active form of folate, and other folate derivatives can cause DNA damage by decomposing to produce formaldehyde. Using powerful gene editing technology they created cells where the 1C cycle is inactivated, and using these cells they confirmed that the release of formaldehyde following THF exposure was because of the decomposition of the vitamin rather than its role in stimulating the 1C cycle. The 1C cycle is essential for cellular life and the cells that Guillermo Burgos Barragan and Niek Wit created where this cycle does not function do not grow unless they are provided the end products of the cycle in their growth medium. However, if these factors are removed and replaced with just formaldehyde then remarkably these defective cells are able to grow. This is because the tier 1 protection enzyme ADH5 converts the toxic formaldehyde into formate, a much less reactive chemical that cells use to make some of the building blocks of life that the normal 1C cycle was previously capable of making. Furthermore, using a combination of formaldehyde isotope labelling with mass spectrometry, this formaldehyde can be traced into the creation of the bases that make DNA.

This new research has several implications. Formaldehyde, which is apparently ubiquitous in our environment and lifestyles, is a well-known toxin to humans. However, most of this chemical comes from within our bodies and this work identifies how and where some of this formaldehyde is coming from. Moreover, this endogenously produced formaldehyde is harnessed by our cells to produce some of the building blocks of life – a process by which a dangerous reactive toxin is converted into a benign and useful chemical. Finally, targeting the physiological source of 1C units has been believed to be a promising target in cancer cells, however this study now suggests that such cells may be able to bypass such approaches by using the new formaldehyde cycle discovered in this work.

This work was funded by the MRC, Cancer Research UK and the Wellcome Trust.

Further references:

Paper in Nature
KJ’s group page
Alexei Vazquez’s group page
Chris Chang’s group page
MRC Press Release
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