RNA Modification and Mitochondrial Diseases
Our research is focused on RNA modification and its relationships with mitochondrial and infectious diseases.
Post-transcriptional modification of transfer and ribosomal RNAs (tRNAs and rRNAs, respectively) plays an important role in optimizing their functions as core molecules of the protein synthesis apparatus. Moreover, recent data support the notion that RNA modifications and RNA modifying enzymes may work as checkpoints for integrating protein synthesis with other cellular functions, and also as regulators of gene expression.
Defects in the modification of mitochondrial (mt) tRNAs have been associated with several neuromuscular diseases (e.g., MERRF and MELAS), acute infantile liver failure, and infantile hypertrophic cardiomyopathy. Our work contributes to the biochemical, structural and functional characterization of several families of evolutionarily conserved enzymes involved in the modification of both mitochondrial and bacterial tRNAs. We use a wide range of biological models (bacteria, yeast, nematodes, human cell lines) and approaches (Molecular Biology, Biochemistry, Microbiology, Cell Biology, Structural Biology and Bioinformatics) to obtain information on the mechanisms used by tRNA-modifying enzymes to perform their functions and to control gene expression. Our research may help to gain a better understanding of the pathophysiological mechanisms leading to the aforementioned diseases and to develop new therapeutic treatments. We collaborate with CIBERER (Biomedical Research Networking Centre in Rare Diseases) groups to achieve these aims.
Modification of tRNA and rRNA is also closely related to bacterial virulence and resistance to antibiotics and stresses. Our group has identified and characterized several RNA modifying enzymes which are involved in translational fidelity, adaptability of bacteria to stress conditions, and activation of mechanisms promoting maintenance and spread of antibiotic-resistant bacteria. We believe it is possible to exploit this knowledge for the choice of therapeutic strategies and design of new drugs.
The ROS-sensitive microRNA-9/9* controls the expression of mitochondrial tRNA-modifying enzymes and is involved in the molecular mechanism of MELAS syndrome.
Meseguer S, Martínez-Zamora A, García-Arumí E, Andreu AL, Armengod ME
Human molecular genetics , 2015 Jan 1, vol. 24, pag. 167-84
The output of the tRNA modification pathways controlled by the Escherichia coli MnmEG and MnmC enzymes depends on the growth conditions and the tRNA species.
Moukadiri I, Garzón MJ, Björk GR, Armengod ME
Nucleic acids research , 2014 Feb, vol. 42, pag. 2602-23
The tRNA-modifying function of MnmE is controlled by post-hydrolysis steps of its GTPase cycle.
Prado S, Villarroya M, Medina M, Armengod ME
Nucleic acids research , 2013 Jul, vol. 41, pag. 6190-208
Evolutionarily conserved proteins MnmE and GidA catalyze the formation of two methyluridine derivatives at tRNA wobble positions.
Moukadiri I, Prado S, Piera J, Velázquez-Campoy A, Björk GR, Armengod ME
Nucleic acids research , 2009 Nov, vol. 37, pag. 7177-93
Characterization of human GTPBP3, a GTP-binding protein involved in mitochondrial tRNA modification.
Villarroya M, Prado S, Esteve JM, Soriano MA, Aguado C, Pérez-Martínez D, Martínez-Ferrandis JI, Yim L, Victor VM, Cebolla E, Montaner A, Knecht E, Armengod ME
Molecular and cellular biology , 2008 Dec, vol. 28, pag. 7514-31