FNP First TEAM/2016-1/2

“tRNA Modifications in Human Diseases”

10/2016 – 09/2019

tRNA Modifications in Human Diseases

What is the project about?

Living organisms, including humans, require so called enzymes to carry out all essential cellular functions needed for survival, reproduction and adaptation to changing environmental conditions. The blueprints for the production of these specialized cellular machines are encoded in the genomic deoxyribonucleic acid (DNA) of each individual cell in our body. Cells use information stored in DNA to (i) produce messenger ribonucleic acid (mRNA) molecules and (ii) employ transfer RNA (tRNA) molecules to translate these mRNAs into correctly assembled chains of amino acids. Once these chains are produced correctly, they fold into their three dimensional structure that allows them to carry out their specialized function. The structure is different for every protein, it depends on the sequence of the incorporated amino acids and it is adapted to the respective enzymatic activities. In this FirstTEAM project we are interested in understanding the molecular details of specific tRNA modification reactions leading to the addition of small chemical groups. These subtle changes have strong influence on the correct production of properly folded and active enzymes. In detail, our aim is to uncover the structure, organization and regulation of molecular machineries that conduct these modification reactions and characterize their activity. Strikingly, patients suffering from certain types of cancer and neurodegenerative diseases often carry mutations in the proteins that are components of these complexes. Therefore, it is of prime scientific and clinical importance to study these evolutionary highly conserved mechanisms. Our work will not only clarify their role in normal healthy cells, but is also necessary to understand their contribution during the onset of various diseases.

How will we get to the results?

We will use a combination of structural biology, biochemistry, biophysics and cell biology to investigate the structure and function of the involved enzymatic cascades. The structural snapshots of the enzymes at atomic level will not only allow us to explain how these cellular machines work, but also to design specific drugs that can block, restore or enhance their activity. In addition, we plan to create human cell lines that allow us to specifically activate or deactivate these modification reactions in the living cells. These cellular models will enable us to study the specific role of the individual enzymes and to understand the communication between different modification pathways. Last but not least, we will investigate potential treatment strategies in these cellular disease models to pave the way for novel therapeutic approaches.

How will the results influence future research and therapeutic strategies?

The results of this project will provide deep insights into cellular mechanisms that help us and the cells of our body to properly respond and adapt to environmental and metabolomic changes or stress. Our current view is that the mechanisms under investigation protect ourselves and our cells, in particular our neurons, from several serious illnesses. Our research will unravel novel therapeutic targets and intervention strategies for cancer and rare neurodegenerative diseases. Using a combination of different molecular biology and cell biology methods we will develop and establish techniques that allow a systematic screening to identify novel lead compounds and drug candidates.

Team Members

Sebastian Glatt (PI)

Anna Biela (postdoc)

Marta Smejda (PhD student)

Mikołaj Sokołowski (PhD student)

Keerthiraju Ethiraju Ravichandran (PhD student)

Dominika Kądziołka (Research Technician)

Andrzej Chramiec Głąbik (Research Technician)

Budget

1 998 789,00 PLN

+ 830 700,00 PLN Anaerobic Crystallization Robot

Publications

  • Krutyhołowa R*, Zakrzewski K* and Glatt S; Structure and Function of tRNA modifiers (in press, Curr Opin Struct Biol. 2019)
  • Hawer H*, Hammermeister A*, Ravichandran KE*, Glatt S, Schaffrath R, Klassen R, Roles of Elongator Dependent tRNA Modification Pathways in Neurodegeneration and Cancer; Genes 2018 Dec 28;10(1)
  • Kojic M, Gaik M, Kiska B, Salerno-Kochan A, Hunt S, Tedoldi A, Mureev S, Jones A, Whittle B, Genovesi LA, Adolphe C, Brown DL, Stow JL, Alexandrov K, Sah P, Glatt S*, Wainwright BJ*; Elongator mutation in mice induces neurodegeneration and ataxia-like behavior; Nat Comm. 2018 Aug;9(1)
  • Lin TY and Glatt S, tRNA modification by Elongator protein 3 (Elp3), Encyclopedia of Inorganic and Bioinorganic Chemistry 2018 (book chapter)
  • Sokołowski M*, Klassen R*, Bruch A, Schaffrath R, Glatt S; Cooperativity between different tRNA modifications and their modification pathways; Biochim Biophys Acta. 2018 Apr;1861(4)
  • Dauden MI*, Jaciuk M*, Müller CW, Glatt S; Structural asymmetry in the eukaryotic Elongator complex, FEBS Lett. 2017 Sep;592(4)