TRMT1-Catalyzed tRNA Modifications Are Required for Redox Homeostasis To Ensure Proper Cellular Proliferation and Oxidative Stress Survival

ABSTRACT

Mutations in the tRNA methyltransferase 1 (TRMT1) gene have been identified as the cause of certain forms of autosomal-recessive intellectual disability (ID). However, the molecular pathology underlying ID-associated TRMT1 mutations is unknown, since the biological role of the encoded TRMT1 protein remains to be determined. Here, we have elucidated the molecular targets and function of TRMT1 to uncover the cellular effects of ID-causing TRMT1 mutations. Using human cells that have been rendered deficient in TRMT1, we show that TRMT1 is responsible for catalyzing the dimethylguanosine (m2,2G) base modification in both nucleus- and mitochondrion-encoded tRNAs. TRMT1-deficient cells exhibit decreased proliferation rates, alterations in global protein synthesis, and perturbations in redox homeostasis, including increased endogenous ROS levels and hypersensitivity to oxidizing agents. Notably, ID-causing TRMT1 variants are unable to catalyze the formation of m2,2G due to defects in RNA binding and cannot rescue oxidative stress sensitivity. Our results uncover a biological role for TRMT1-catalyzed tRNA modification in redox metabolism and show that individuals with TRMT1-associated ID are likely to have major perturbations in cellular homeostasis due to the lack of m2,2G modifications.

KEYWORDS:

• RNA
• TRMT1
• Trm1
• dimethylguanosine
• intellectual disability
• methylation
• methyltransferase
• modification
• neurodevelopment
• tRNA modification

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at https://doi.org/10.1128/MCB.00214-17.

ACKNOWLEDGMENTS

We thank Elaine Sia, Sina Ghaemmaghami, and Eric Phizicky for comments on the manuscript and Jillian Ramos, Christopher Prevost, and Rebecca Galer for technical assistance.

This work was supported by a Liebig Fellowship from Fonds of Chemical Industries and a LMU Junior Research Fund to S.M.K., as well as a University of Rochester Furth Fund Award and NSF CAREER award 1552126 to D.F.