Abstract
Over 14,000 Americans die each year from kidney cancer with clear-cell Renal Cell Carcinoma (ccRCC) being the most prevalent and malignant type of kidney cancer. Recent work has implicated disruptions in glutathione (GSH) metabolism as predictors of poor survival in ccRCC. Maintenance of the GSH redox cycle is reliant on the activities of selenocysteine-containing GSH metabolizing enzymes whose translation is controlled by the alkylation repair homolog 8 (Alkbh8) tRNA methyltransferase. In cells from Alkbh8-/- mice the absence of the tRNA methyltransferase Alkbh8 decreases the levels of many GSH metabolizing selenoproteins, promotes increased ROS and DNA damage levels, and confers enhanced sensitivity to oxidizing agents. Surprisingly the Alkbh8-/- mice reproduce, thrive normally but display phenotypic characteristics of premature ageing such as weight loss, reduced subcutaneous fat, alopecia (hair loss), kyphosis (curvature of the spine) when compared to their aged-matched WT control. Alkbh8-deficiency also triggers a senescence and metabolic gene signature that is predictive (Hazard Ratio 2.94, p
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