Novel targets of formaldehyde toxicity in cancer cells

LUCAS B. PONTEL

Parana

Congreso; Annual Meeting of the Argentinean Society for Research in Biochemistry and Molecular Biology; 2018

SAIB

Fundamental metabolism provides energy and molecules required for cell growth and development. Some biological reactions such as histone and nucleic acid demethylations or the one carbon cycle can also generate genotoxic metabolites such as endogenous formaldehyde (EFA). This simple aldehyde avidly reacts with electron-rich groups adducting proteins, nucleic acids and thiols. To prevent EFA toxicity, mammals harbour the enzyme alcohol dehydrogenase 5 (ADH5) that converts EFA into the less reactive molecule formate. The Fanconi Anemia DNA repair pathway protects the genome from EFA-induced DNA damage. The inactivation of these two systems in mice leads to hematopoietic stem cell loss, karyomegaly, liver and kidney dysfunction, and cancer, revealing the cytotoxic and carcinogenic potential of EFA. DNA damage is likely one of the main drivers of EFA toxicity, however the strong reactivity of EFA may affect other cellular targets and biomolecules. To further understand how EFA damages cells, we have established a colorectal carcinoma cancer model deficient in ADH5. These cells are exquisitely sensitive to EFA, which also alters the formation of in vitro tumour spheroids. The characterization of ADH5-deficient cells uncovers novel targets of EFA toxicity and a conserved protection mechanism to counteract the most simple and one of the most reactive endogenous aldehydes