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WHAT ARE WE STUDYING?
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, as illustrated by the figure below.
Cancer and tRNA modification enzymes. List of up (red) or down (blue) regulated tRNA modification enzymes associated with various forms of cancer in humans. Image adapted from Sarin & Leidel, RNA Biology, 2014.
WHY ARE WE STUDYING IT AND HOW CAN YOU HELP?
Our research aims to understand the basic mechanisms by which tRNA modifications influence translation and, specifically, how these modifications modulate translation upon infection. To this end, we study both the host and the pathogen in order to map their tRNA modification levels and monitor their translation as infection progresses. Using state-of-the-art techniques, such as nano-flow RNA mass spectrometry and ribosome profiling, we are making the first comprehensive inventory of tRNA modification levels during infection and pinpointing the key modulators of translation.
We are also keen to determine which tRNA modifications that are essential for immunity and pathogenicity. Loss of 2′-O-methylation in tRNA perturbs immunity in plants, making them susceptible to bacterial infection. Conversely, 2-thiolation of tRNA increases pathogenicity in bacteria and yeast. Utilising our inventory of tRNA modifications, we will identify additional tRNA modifications that are pathogenicity factors and verify these findings using our model organisms.
We are also fascinated by viruses that encode their own tRNAs. The function of these viral tRNAs is unknown, although it is hypothesized they supplement for codons that are common in the viral genome but rare in the host. If so, then the viral tRNAs must be properly processed, charged, and modified in order to partake in translation. We intend to elucidate this by identifying the modifications, determining their position on the molecule, and by means of overexpression studies, analyse the effect of these viral tRNAs on translation.
How can you help?
Our research strives to answer fundamental questions concerning translation. Although our research will not cure cancer nor provide alleviation for those suffering from tRNA-related diseases, it does provide vital knowledge to the foundation upon which future discoveries are made. Your contribution will help to ensure that these aims are achieved, and that we better understand what is happening in our own cells. Please follow this link or click on the banner below for detailed instructions on how to contribute. For further information about our research and its impact, please contact Principal Investigator Peter Sarin.
WHO ARE WE?
We are the RNAcious Laboratory, a recently founded research group at the Department of Biosciences at the University of Helsinki. For more information about us, please visit our team homepage.