How does RNA structure govern messenger RNA function? Completion of the research project.

Dr. Leszek Błaszczyk from the Department of Structure and Function of Biomolecules has completed his research in the project entitled “How RNA structure governs messenger RNA function? Exploring structural and functional aspects essential for synthesis of p53 protein – a master regulator of vital cellular functions” (grant no: 2016/23/D/NZ1/02565).

p53 is a protein involved in almost every aspect of cell functioning. In response to various stress factors such as DNA damage, oncogene activation, or oxidative stress, p53 activates the expression of hundreds of genes, ultimately leading to the inhibition of cell division or apoptosis. This allows for an attempt to repair damages or, when it is impossible, to eliminate a potentially dangerous cell from the organism. Therefore, mutations in the p53 gene most commonly lead to tumorigenesis. Due to the role the p53 protein plays in the cell, its expression is tightly regulated at multiple stages. One of these stages involves the regulation of translation initiation through RNA-RNA interactions that occur between the non-coding regions of p53 mRNA at the 5′ and 3′ ends. Although the mechanism of direct pairing of distant fragments of p53 mRNA is unknown, it enables the stimulation of p53 protein translation under conditions of DNA damage-induced stress, thereby protecting the cell from negative consequences such as, for example, tumorigenesis. This mode of translation regulation is unique in the world of eukaryotic organisms and has so far only been described in bacteria and viruses.

One of the project goals was investigation how distant regions of p53 mRNA interact directly and understanding the role of proteins in this process. The research has demonstrated, for the first time, that one of the factors regulating p53 protein translation, nucleolin, exhibits RNA chaperone activity, thereby promoting long-range interactions between the non-coding regions of 5′ and 3′ p53 mRNA. Through extensive biochemical and mutational analysis, structural motifs in p53 mRNA that play a crucial role in the formation of this interaction have been identified. Based on the above findings, a model describing the nucleolin-dependent long-range interaction in p53 mRNA has been proposed. The model not only explains this remarkably interesting mode of translation regulation but also sheds new light on previous results of functional research.

The results obtained during the implementation of this project significantly expanded the knowledge on the relationship between RNA structure and function, in particular in the context of RNA structure’s role in the process of translation regulation. They also provided structural data that may be useful in the development of potential anti-cancer therapies targeting functionally important regions of p53 mRNA.

The results of the project have been published in the RNA Journal:

“Exploring structural determinants and the role of nucleolin in formation of the long-range interactions between untranslated regions of p53 mRNA”. Agnieszka Kiliszek, Wojciech Rypniewski, Leszek Błaszczyk, RNA Journal, 2023 May;29(5):630-643. doi: 10.1261/rna.079378.122

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