Thinking out of the BOX

Why should we care about tRNA modification? Transfer RNA (tRNA) is at the heart of translation — the process at which the genetic code of an organism is deciphered into functional machines, i.e. proteins. In this process, the tRNA molecules work as adapters that proof read the code and, upon a successful match, add the correct amino acids, i.e. the building blocks that make up proteins. For this intricate process to function correctly, tRNA molecules need to be chemically modified at key positions of the molecule. This is achieved by specialised tRNA modification enzymes acting alone or as part of complex pathways. These chemical modifications provide structural integrity to the tRNA molecule and more importantly, they regulate the accuracy and speed of translation. Despite their crucial role in a core function of life, we are only beginning to understand the vast implications of tRNA modification and the complexity of the underlying mechanisms. We know that in single-celled eukaryotes, such as yeast, tRNA modifications are seldom required when the growth conditions are optimal. However, once a yeast cell lacking proper tRNA modification encounters any form of stress, severe problems in stress response systems, protein homeostasis, etc. start to emerge. The more complex the organism, the more severe the implications. In humans, a fault in only one mitochondrial tRNA modifying enzyme gives rise to severe developmental disorders, as manifested in the MERFF and MELAS syndromes. Problems in amino acid charging of tRNA molecules causes neurodegenerative diseases, such as ALS. Moreover, incorrect regulation of tRNA modification enzymes has been associated with breast cancer and various other forms of cancer