Selenocysteine tRNA methylation promotes oxidative stress resistance in melanoma metastasis

Selenocysteine-containing proteins play a central role in redox homeostasis. Their translation is a highly regulated process dependent on two tRNASec isodecoders differing by a single 2'-O-ribose methylation, called Um34. We characterized FTSJ1 as the Um34 methyltransferase and show that its activity is required for efficient selenocysteine insertion at the UGA stop codon during translation. Specifically, loss of Um34 leads to ribosomal stalling and decreased UGA recoding. FTSJ1-deficient cells are more sensitive to oxidative stress and have decreased metastatic colonization in xenograft models of melanoma metastasis. Our findings uncover a role for tRNASec Um34 modification in oxidative stress resistance and highlight FTSJ1 as a potential therapeutic target specific for metastatic disease. ### Competing Interest Statement LED is an advisor and holds equity in Mirimus Inc. and is a consultant for Volastra Therapeutics and Frazier Healthcare Partners. The other authors have no conflicts to disclose.