How to make a protein from methylated mRNA

“Transcription” is a cellular process that allows genetic information to flow from DNA to mRNA. During a subsequent step, called “translation”, the resulting mRNA molecules are translated into amino acid chains that fold into cellular proteins and carry out almost all functions in our bodies. This basic principle becomes more intricate by the existence of naturally occurring RNA modifications, and extensive scientific efforts around the globe are underway to decipher their precise role. The latest work of scientists from the Malopolska Center of Biotechnology of the Jagiellonian University revealed the mechanistic effects of a specific mRNA modification, namely N6 adenine methylation (m6A), on the translation process. The results were obtained in collaboration with a group at Max Planck Institute in Göttingen and recently published in “Nature Communications”.

Structural biologists from the Max Planck Research Group at the MCB JU in collaboration with biophysicists at the Max Planck Institute in Göttingen investigated the role of mRNA adenine methylation (m6A). During ribosomal decoding, the mRNA sequence needs to be recognized by appropriate transfer RNAs (tRNAs). tRNAs deliver amino acids to the growing polypeptide chain that eventually becomes a functional protein. According to the complementary results of the study, the mRNA modification enhances tRNA drop-off rates from the ribosome, by which cells could slow down the production of specific proteins. The study addresses a fundamental biological question, as m6A is the most common mRNA modification found in nature. The addition of the methyl moiety is regulated by the cell and has been linked to numerous important physiological processes and human pathologies, including cancer.

It is a challenging task to observe structural changes of a tiny molecular moiety, like a single methyl group constituting only a single carbon atom and three hydrogens. Thanks to the MCB Structural Biology Core Facility and the cryo-electron microscope Titan Krios G3i located at the Jagiellonian University SOLARIS National Synchrotron Radiation Centre, the researchers in Krakow resolved the atomic details of the translating ribosomes, allowing them to monitor the influence of m6A modification during the translation process. “While the ribosome is one of the most extensively studied and described macromolecular machines, it is surprising and exciting to discover new aspects of the inner workings of this complex biological machinery”, says Dr Lukasz Koziej, one of the first authors of the study. Dr Glatt, one of the two corresponding authors, adds “It is satisfying to reveal such a minute modifications at work. The combination of structural biology and biophysics brings us much closer to understand the role of other complex RNA modifications.”

The research at MCB was supported by grants from European Research Council (ERC) and the Foundation for Polish Science (FNP).

Artwork by Dominika Dobosz (MCB/UJ)
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