Hydrophobic amino acids chart
Finally, Elongator and other U 34-enzymes were identified as a key determinant of gemcitabine sensitivity in gallbladder cancer by regulating the mRNA translation of hnRNPQ 26. Furthermore, U 34-enzymes promote resistance to targeted therapy in melanoma, through regulation of HIF1A mRNA translation in a codon-dependent manner 19. Also, U 34-enzymes regulate breast cancer metastasis through the translation of the pro-invasive DEK oncoprotein 20. ELP3 was shown to drive Wnt-dependent intestinal tumor initiation by maintaining a subpopulation of Lgr5 +/Dclk1 +/Sox9 + cancer stem cells 25.
![hydrophobic amino acids chart hydrophobic amino acids chart](https://pubs.rsc.org/image/article/2019/NA/c9na00498j/c9na00498j-c1_hi-res.gif)
In cancer, we and others have recently uncovered a key role of U 34-enzymes in tumor development, metastasis and resistance to therapy by promoting efficient codon-specific translation. Mutations in Elongator genes are associated with neurodegenerative disorders 24. Also, altered proteostasis consequent to Elp3 loss affects the development of the cochlea and results in deafness 23. In particular, loss of the U 34-enzyme Elp3 in murin cortical progenitors results in neurogenesis defects and microcephaly through induction of an unfolded protein response (UPR) 18.
![hydrophobic amino acids chart hydrophobic amino acids chart](https://els-jbs-prod-cdn.jbs.elsevierhealth.com/cms/attachment/423fa84d-4a33-44e6-a15d-dae75fa7680c/gr1_lrg.jpg)
TRNA modifications emerge as key players in development and cancer. However, the mechanisms linking codon-dependent translation dysregulation to protein aggregation remain poorly understood. Recent studies showed that loss of U 34-enzymes leads to increase protein aggregation 17, 19. However, the exact consequences of this codon-specific translation pausing on subsequent protein expression and homeostasis still remain elusive. Ribosome profiling experiments demonstrate that loss of U 34-enzymes leads to ribosome accumulation (i.e., translation elongation defects) mainly at AA-ending codons (i.e., AAA, GAA, CAA) 16, 17, 18, 19. The enzymatic pathway leading to the addition of the mcm 5s 2 modification at U 34-tRNAs (U 34-enzymes) encloses the acetyltransferase complex Elongator, a six subunit complex (ELP1-6) where ELP3 harbors the catalytic activity, the methyltransferase ALKBH8 (Alkylation repair homolog 8) and the thiouridylase complex composed of CTU1/2 proteins (Cytosolic thiouridylase proteins 1/2) 12, 14, 15, 21, 22. Consequently, loss of these modifications was shown to lower expression of functionally important proteins whose mRNA is enriched in such codons, a process that can be rescued by the replacement of AA-ending codons by synonymous, U 34-tRNA modification independent, AG-ending codons 19, 20. In this context, wobble uridine (U 34) tRNA modifications, including the addition of both methoxycarbonylmethyl (mcm 5) and thiol (s 2), are crucial for the decoding of specific codons, mainly AA-ending codons (i.e., AAA, GAA, CAA) 12, 13, 14, 15, 16, 17, 18, 19. Local translation elongation rate is tightly regulated at the level of individual codons through the integration of different layers, including tRNA abundance and modification, tRNA selection, and codon usage. In addition, cells must not only promote accurate folding but also have to prevent accumulation of misfolded proteins that may arise from errors in translation, aberrant mRNAs, or defects in the chaperone machinery 10, 11. The speed of ribosomes on mRNA during translation is not uniform and an increasing amount of evidence has demonstrated that translation kinetics play a prominent role in proteostasis by impacting co-translational protein folding, translation fidelity, or protein quality control pathways 1, 2, 3, 4, 5, 6, 7, 8, 9. mRNA translation impacts protein output, but it also regulates co-translational processes that assist nascent polypeptides. Together, these results uncover the mechanism linking wobble tRNA modification to mRNA translation and aggregation to maintain proteome homeostasis.Īdequate regulation of mRNA translation rate and speed is essential for cellular homeostasis. Accordingly, the combination of codon content and the presence of hydrophilic motifs define the proteome whose maintenance relies on U 34-tRNA modification. Specific hydrophilic motifs cause protein aggregation and degradation upon codon-dependent translation elongation defects. While translation defects upon perturbation of U 34-enzymes are strictly dependent on codon content, the consequences on protein output are determined by other features.
![hydrophobic amino acids chart hydrophobic amino acids chart](http://2.bp.blogspot.com/-UlQkpK3n7vA/UUv1YwKYEoI/AAAAAAAAAbw/pNx5Af_oBk4/s1600/amino+acids+nonpolar.jpg)
Using knockdown models of enzymes that catalyze the mcm 5s 2 wobble uridine tRNA modification (U 34-enzymes), we show that gene codon content is necessary but not sufficient to predict protein fate. Here, we investigate features linking regulation of codon-dependent translation elongation to protein expression and homeostasis. Regulation of mRNA translation elongation impacts nascent protein synthesis and integrity and plays a critical role in disease establishment.