RNA, Transfer; Thioredoxins
In mice and humans some tRNAs are exclusively encoded as intron-containing genes, thus highlighting the importance of tRNA splicing as an essential process. Introns are excised in the nucleus by the tRNA splicing endonuclease (TSEN) complex. The resulting exon halves are subsequently ligated to generate mature tRNAs. We have combined chromatography, mass spectrometry, RNAi and phylogenetic analysis to identify key components of the human tRNA splicing pathway, and discovered the RNA kinase CLP1 as part of the TSEN complex (S. Weitzer and J. Martinez, 2007). We also discovered the tRNA ligase complex which has been elusive for 30 years, established RTCB/HSPC117 as the catalytic subunit (J. Popow et al., 2011 and 2012), and archease as an essential co-factor of the tRNA ligase complex (J. Popow et al., 2014).
Recently we showed that the tRNA ligase and archease play critical roles in the unfolded protein response and that CLP1, when mutated, causes neurological diseases both in humans and mice. We have also revealed the sensitivity of the tRNA ligase complex to oxidative stress and identifed a novel RNA cyclic phosphatase in human cells.
Techniques, methods & infrastructure
biochemistry, molecular and cellular biology, mouse models.
- Jurkin, J. et al., 2014. The mammalian tRNA ligase complex mediates splicing ofXBP1mRNA and controls antibody secretion in plasma cells. The EMBO Journal, 33(24), pp.2922-2936. Available at: http://dx.doi.org/10.15252/embj.201490332.
- Karaca, E. et al., 2014. Human CLP1 Mutations Alter tRNA Biogenesis, Affecting Both Peripheral and Central Nervous System Function. Cell, 157(3), pp.636-650. Available at: http://dx.doi.org/10.1016/j.cell.2014.02.058.
- Popow, J. et al., 2014. Analysis of orthologous groups reveals archease and DDX1 as tRNA splicing factors. Nature, 511(7507), pp.104-107. Available at: http://dx.doi.org/10.1038/nature13284.
- Popow, J. et al., 2011. HSPC117 Is the Essential Subunit of a Human tRNA Splicing Ligase Complex. Science, 331(6018), pp.760-764. Available at: http://dx.doi.org/10.1126/science.1197847.
- Weitzer, S. & Martinez, J., 2007. The human RNA kinase hClp1 is active on 3′ transfer RNA exons and short interfering RNAs. Nature, 447(7141), pp.222–226. Available at: http://dx.doi.org/10.1038/nature05777.