ADH5 forms a novel pathway that sustains cellular redox balance in cancer cells

MARCO ADRIÁN SCHEIDEGGER; CARLA UMANSKY; AGUSTIN MORELLATO; LUCAS PONTEL

Mar del Plata

Congreso; Reunión Anual de Sociedades de Biociencia; 2019

Sociedad Argentina de Investigación Clínica

Fundamental metabolism provides energy and precursor molecules required for cell growth and development. Some biological processes such as histone and nucleic acid demethylations or the one carbon cycle can also generate surplus genotoxic metabolites such as endogenous formaldehyde (FA). This simple aldehyde avidly reacts with electron-rich groups, adducting proteins, nucleic acids and thiol-rich components like glutathione (GSH) and thus threatening cell integrity. Here, we show that cancer cells harbour specific systems to prevent cellular redox imbalance caused by FA. These systems are centred on the enzyme alcohol dehydrogenase 5 (ADH5) that converts FA into the less reactive molecule formate. Inactivation of ADH5 by CRISPR/Cas9 renders colorectalcarcinoma cells severely sensitive to FA showing early induction of apoptosis, DNA damage and oxidative stress. Mechanistically, FA triggers a phosphorylation cascade that leads to cell cycle arrest and cell death, which is prevented by the inactivation of the tumour suppressor P53. Overall, this work characterizes the response of cancer cells to FA and the role of ADH5 in preventing FA cytotoxicity, which might have wide implications for Fanconi Anemia and Ruijs?Aalfs syndrome patients, and for cancer development in carriers of BRCA2 mutations, all diseases whose onset is associated to endogenous FA.