ADH5 and glutathione biosynthesis prevent formaldehyde toxicity in cáncer cells

MARCO ADRIÁN SCHEIDEGGER; CARLA UMANSKY; HERNAN REINGRUBER; LUCAS PONTEL

CABA

Simposio; Max Planck Scientific Advisory Board; 2019

Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck (IBioBA-MPSP)

Formaldehyde (FA) is an environmental human carcinogen that can be generated endogenously from fundamental biochemical reactions such as demethylation of histones and nucleic acids, and the folate metabolism. The diet (methanol-containing food, aspartame and juice pectins) can also contribute with circulating FA. This aldehyde strongly reacts with electron-rich groups present in nucleic acids and proteins causing several lesions such as base and protein adducts, DNA-interstrand crosslinks (ICLs) and DNA-protein crosslinks (DPCs). To cope with FA, organisms have evolved two systems of protection: FA detoxification (via the ADH5 enzyme) and DNA-crosslink repair (via the Fanconi Anemia DNA repair pathway). FA is likely to react with one of the most abundant cellular thiols ?Glutathione (GSH)- although it is not clear whether GSH prevents FA toxicity. Here, we show that the spontaneous reaction between FA and GSH limits FA toxicity and at the same time reduces the level of cellular GSH. The genetic inactivation of ADH5 and the pharmacological inhibition of GSH biosynthesis shed light into the mechanism of protection against FA. The implications of this mechanism for cell physiology as well as the design of a genetic knock-down system to silence GSH-biosinthesis are discussed.