Thursday, November 21, 2024
11/21/2024
Maintenance of the GSH redox cycle is reliant on the activities of selenocysteine-containing GSH metabolizing enzymes which play fundamental roles in chemoprevention. Selenocysteine is the 21st amino acid and does not contain a dedicated codon. Selenocysteine incorporation during translation requires UGA-stop-codon recoding, which uses specifically modified tRNA for accurate decoding. Dynamic changes in tRNA modification are an epitranscriptomic signal because they regulate gene expression post-transcriptionally. We have shown that the stress-induced translation of many selenocysteine containing ROS detoxifying enzymes is dependent on the Alkbh8 tRNA methyltransferase. Alkbh8 enzymatically methylates the uridine wobble base on tRNASelenocysteine to promote UGA-stop codon decoding. We have developed an Alkbh8 deficient mouse and have used molecular, biochemical, and genomic approaches to demonstrate that Alkbh8Def mouse embryonic fibroblasts (MEFs) and some organs display markers of senescence and a senescence gene signature. Using human cells and our new Alkbh8Def/p16-3MR mice we propose to test the hypothesis that senescence occurs in vitro and in vivo because of defective epitranscriptomic signals that controls selenocysteine utilization. To achieve this two aims will: 1. determine if Alkbh8 and other epitranscriptomic writers that limit selenocysteine utilization restrict the senescence program and 2. determine if Alkbh8-deficiency drives senescence in vivo and whether senescence ablation accelerates or tempers pathologies that accompany selenoprotein loss. Our proposal is being submitted with significant preliminary data supporting the idea that Alkbh8 and epitranscriptomic signals are key to chemoprevention by limiting senescent activity.
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