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*612694
Table of Contents
Alternative titles; symbols
HGNC Approved Gene Symbol: CTU1
Cytogenetic location: 19q13.41 Genomic coordinates (GRCh38) : 19:51,097,606-51,108,409 (from NCBI)
Modified nucleosides close to the anticodon in tRNAs are important for proper decoding of mRNA by the ribosome. Particularly, thiolation of the wobble uridine at position 34 (U34) of tRNA-lys(UUU) (see 189918), tRNA-glu(UUC) (see 180640), and tRNA-gly(UUG) (see 189911) occurs in nearly all species. CTU1 is a subunit of a highly conserved protein complex involved in thiolation of wobble U34 (Dewez et al., 2008).
By database analysis, Dewez et al. (2008) identified human CTU1 based on its homology with its fission yeast ortholog. The deduced 348-amino acid protein contains an evolutionarily conserved P-loop motif.
By sequencing proteins that interacted with URM1 (612693), followed by database analysis and PCR of a HeLa cell cDNA library, Schlieker et al. (2008) cloned ATPBD3. Endogenous ATPBD3 migrated at an apparent molecular mass of 38 kD by SDS-PAGE.
Schlieker et al. (2008) showed that human ATPBD3 thiolated uracils on tRNAs with URM1 functioning as the sulfur carrier intermediate. Knockdown of either URM1 or ATPBD3 in HeLa cells reduced thiolation of uracil in the anticodon region of tRNA-lys(UUU) (see TRNAK1, 189918).
Rapino et al. (2018) showed in humans that the enzymes that catalyze modifications of wobble uridine-34 (U34) tRNA are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAF V600E (164757.0001) oncogene and by resistance to targeted therapy in melanoma. Rapino et al. (2018) showed that BRAF V600E-expressing melanoma cells are dependent on U34 enzymes for survival, and that concurrent inhibition of MAPK signaling and ELP3 (612722) or CTU1 and/or CTU2 (617057) synergizes to kill melanoma cells. Activation of the PI3K signaling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U34 enzymes. Mechanistically, U34 enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A (603348) mRNA and the maintenance of high levels of HIF1-alpha protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U34 enzymes and HIF1-alpha. Rapino et al. (2018) concluded that U34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation.
Hartz (2009) mapped the ATPBD3 gene to chromosome 19q13.33 based on an alignment of the ATPBD3 sequence (GenBank BC009037) with the genomic sequence (build 36.1).
Dewez, M., Bauer, F., Dieu, M., Raes, M., Vandenhaute, J., Hermand, D. The conserved wobble uridine tRNA thiolase Ctu1-Ctu2 is required to maintain genome integrity. Proc. Nat. Acad. Sci. 105: 5459-5464, 2008. [PubMed: 18391219, images, related citations] [Full Text]
Hartz, P. A. Personal Communication. Baltimore, Md. 3/25/2009.
Rapino, F., Delaunay, S., Rambow, F., Zhou, Z., Tharun, L., De Tullio, P., Sin, O., Shostak, K., Schmitz, S., Piepers, J., Ghesquiere, B., Karim, L., and 17 others. Codon-specific translation reprogramming promotes resistance to targeted therapy. Nature 558: 605-609, 2018. Note: Erratum: Nature 599: E14, 2021. [PubMed: 29925953, related citations] [Full Text]
Schlieker, C. D., Van der Veen, A. G., Damon, J. R., Spooner, E., Ploegh, H. L. A functional proteomics approach links the ubiquitin-related modifier Urm1 to a tRNA modification pathway. Proc. Nat. Acad. Sci. 105: 18255-18260, 2008. [PubMed: 19017811, images, related citations] [Full Text]
Alternative titles; symbols
HGNC Approved Gene Symbol: CTU1
Cytogenetic location: 19q13.41 Genomic coordinates (GRCh38) : 19:51,097,606-51,108,409 (from NCBI)
Modified nucleosides close to the anticodon in tRNAs are important for proper decoding of mRNA by the ribosome. Particularly, thiolation of the wobble uridine at position 34 (U34) of tRNA-lys(UUU) (see 189918), tRNA-glu(UUC) (see 180640), and tRNA-gly(UUG) (see 189911) occurs in nearly all species. CTU1 is a subunit of a highly conserved protein complex involved in thiolation of wobble U34 (Dewez et al., 2008).
By database analysis, Dewez et al. (2008) identified human CTU1 based on its homology with its fission yeast ortholog. The deduced 348-amino acid protein contains an evolutionarily conserved P-loop motif.
By sequencing proteins that interacted with URM1 (612693), followed by database analysis and PCR of a HeLa cell cDNA library, Schlieker et al. (2008) cloned ATPBD3. Endogenous ATPBD3 migrated at an apparent molecular mass of 38 kD by SDS-PAGE.
Schlieker et al. (2008) showed that human ATPBD3 thiolated uracils on tRNAs with URM1 functioning as the sulfur carrier intermediate. Knockdown of either URM1 or ATPBD3 in HeLa cells reduced thiolation of uracil in the anticodon region of tRNA-lys(UUU) (see TRNAK1, 189918).
Rapino et al. (2018) showed in humans that the enzymes that catalyze modifications of wobble uridine-34 (U34) tRNA are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAF V600E (164757.0001) oncogene and by resistance to targeted therapy in melanoma. Rapino et al. (2018) showed that BRAF V600E-expressing melanoma cells are dependent on U34 enzymes for survival, and that concurrent inhibition of MAPK signaling and ELP3 (612722) or CTU1 and/or CTU2 (617057) synergizes to kill melanoma cells. Activation of the PI3K signaling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U34 enzymes. Mechanistically, U34 enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A (603348) mRNA and the maintenance of high levels of HIF1-alpha protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U34 enzymes and HIF1-alpha. Rapino et al. (2018) concluded that U34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation.
Hartz (2009) mapped the ATPBD3 gene to chromosome 19q13.33 based on an alignment of the ATPBD3 sequence (GenBank BC009037) with the genomic sequence (build 36.1).
Dewez, M., Bauer, F., Dieu, M., Raes, M., Vandenhaute, J., Hermand, D. The conserved wobble uridine tRNA thiolase Ctu1-Ctu2 is required to maintain genome integrity. Proc. Nat. Acad. Sci. 105: 5459-5464, 2008. [PubMed: 18391219] [Full Text: https://doi.org/10.1073/pnas.0709404105]
Hartz, P. A. Personal Communication. Baltimore, Md. 3/25/2009.
Rapino, F., Delaunay, S., Rambow, F., Zhou, Z., Tharun, L., De Tullio, P., Sin, O., Shostak, K., Schmitz, S., Piepers, J., Ghesquiere, B., Karim, L., and 17 others. Codon-specific translation reprogramming promotes resistance to targeted therapy. Nature 558: 605-609, 2018. Note: Erratum: Nature 599: E14, 2021. [PubMed: 29925953] [Full Text: https://doi.org/10.1038/s41586-018-0243-7]
Schlieker, C. D., Van der Veen, A. G., Damon, J. R., Spooner, E., Ploegh, H. L. A functional proteomics approach links the ubiquitin-related modifier Urm1 to a tRNA modification pathway. Proc. Nat. Acad. Sci. 105: 18255-18260, 2008. [PubMed: 19017811] [Full Text: https://doi.org/10.1073/pnas.0808756105]
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