Epitranscriptomic Control of Selenoprotein Synthesis, Senescence, Mitochondrial Bioenergetics and Clear Cell Renal Cell Carcinoma

Maintenance of the GSH redox cycle is reliant on the activities of selenocysteine-containing GSH metabolizing enzymes. Selenocysteine (SEC) is the 21 st amino acid and does not contain a dedicated codon. SEC incorporation during translation requires UGA-stop-codon recoding, which uses specifically modified tRNA for accurate decoding. We have shown that the stress-induced translation of many SEC containing ROS detoxifying enzymes is dependent on the Alkbh8 tRNA methyltransferase. Alkbh8 enzymatically methylates the uridine wobble base on tRNA SEC to promote UGA-stop codon decoding. In cells from Alkbh8 -/- mice, the absence of the tRNA methyltransferase Alkbh8 decreases the levels off many GSH metabolizing selenoproteins, promotes increased ROS and DNA damage levels, and confers enhanced sensitivity to oxidizing agents. Surprising to us was the ability of the Alkbh8 -/- MEFs and mice to thrive with the functional absence many key SEC containing proteins. Thus, we performed focused gene arrays and biochemical analysis that demonstrated dramatic alterations in both senescence and mitochondrial function. Senescence engagement and bioenergetic reprogramming are commonly observed during carcinogenesis, oncogenic transformation and metastatic disease. Thus, we next evaluated whether the adaptive gene responses that accompany Alkbh8 deficiency may be of prognostic significance. Analysis for the Alkbh8 adaptive genes of illumineseq gene expression data from 37 cancer types in The Cancer Genome Atlas revealed a significant decrease in survival percentage of only patients with the kidney cancer, clear cell renal cell carcinoma and increase of the adapt gene signature with tumor grade. Our observation that global selenoprotein suppression can accelerate the senescence phenotype and bioenergetics function, suggests that SEC-dependent regulation of these processes may be critical for limiting insults that drives tumor development or age related tissue degeneration.