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Ulrich Schweizer, Simon Bohleber, Noelia Fradejas-Villar
Base 37 in tRNA, 3'-adjacent to the anticodon, is occupied by a purine base that is thought to stabilize codon recognition by stacking interactions on the first Watson-Crick base pair. If the first codon position forms an A.U or U.A base pair, the purine is likely further modified in all domains of life. One of the first base modifications found in tRNA is N6 -isopentenyl adenosine (i6 A) present in a fraction of tRNAs in bacteria and eukaryotes, which can be further modified to 2-methyl-thio-N6 -isopentenyladenosine (ms2 i6 A) in a subset of tRNAs...
September 2, 2017: RNA Biology
Kristin D Kernohan, David A Dyment, Mihaela Pupavac, Zvi Cramer, Arran McBride, Genevieve Bernard, Isabella Straub, Martine Tetreault, Taila Hartley, Lijia Huang, Erick Sell, Jacek Majewski, David S Rosenblatt, Eric Shoubridge, Aziz Mhanni, Tara Myers, Virginia Proud, Samanta Vergano, Brooke Spangler, Emily Farrow, Jennifer Kussman, Nicole Safina, Carol Saunders, Kym M Boycott, Isabelle Thiffault
Deleterious variants in the same gene present in two or more families with overlapping clinical features provide convincing evidence of a disease-gene association; this can be a challenge in the study of ultrarare diseases. To facilitate the identification of additional families, several groups have created "matching" platforms. We describe four individuals from three unrelated families "matched" by GeneMatcher and MatchMakerExchange. Individuals had microcephaly, developmental delay, epilepsy, and recessive mutations in TRIT1...
May 2017: Human Mutation
T J Waller, D F Read, D R Engelke, P J Smaldino
TRIT1 is a highly conserved tRNA isopentenyl transferase that modifies a subset of tRNAs in human cells and is a candidate tumor suppressor in lung cancer in certain ethnic populations. The yeast homologue, Mod5, has similar tRNA-modifying functions in the cytoplasm and is required for the transcriptional silencing activity of RNA polymerase II promoters near tRNA genes in the nucleus, a phenomenon termed tRNA gene mediated (tgm) silencing. Furthermore, Mod5 can fold into amyloid fibers in vitro and in vivo, which confers resistance to certain fungicides in yeast...
May 15, 2017: Gene
Qinglu Song, Songtao Yuan, Qin An, Yinyin Chen, Frank Fuxiang Mao, Yizhi Liu, Qinghuai Liu, Guoping Fan
Corneal endothelial cells (CECs) are a monolayer of cells covering the inner-side of cornea, playing a pivotal role in keeping the cornea transparent. Because adult CECs have no proliferative capacity, the loss of CECs during aging or under pathological conditions would lead to corneal edema, eventually leading to the blindness. Clinically, donated CECs have been successfully transplanted to treat the diseases of CEC deficiency; however, the source of CEC donation is very limited. As an alternative cell source for CEC transplantation, CEC-like cells can be obtained via in vitro differentiation of human pluripotent stem cells...
October 2016: Experimental Eye Research
Zhenyu Yue, Hai-Tao Li, Yabing Yang, Sajid Hussain, Chun-Hou Zheng, Junfeng Xia, Yan Chen
Breast cancer (BC) is one of the most common malignancies that could threaten female health. As the molecular mechanism of BC has not yet been completely discovered, identification of related genes of this disease is an important area of research that could provide new insights into gene function as well as potential treatment targets. Here we used subnetwork extraction algorithms to identify novel BC related genes based on the known BC genes (seed genes), gene co-expression profiles and protein-protein interaction network...
June 14, 2016: Oncotarget
Rolf K Swoboda, Rajasekharan Somasundaram, Laura Caputo-Gross, Francesco M Marincola, Paul Robbins, Meenhard Herlyn, Dorothee Herlyn
Noncoding regions of the genome play an important role in tumorigenesis of cancer. Using expression cloning, we have identified a cytotoxic T lymphocyte (CTL)-defined antigen that recognizes a protein sequence derived from an open reading frame transcribed from the reverse strand in the 3' untranslated region of tRNA isopentenyltransferase 1 (TRIT1). A peptide derived from this open reading frame (ORF) sequence and predicted to bind to HLA-B57, sensitized HLA-B57(+) tumor cells to lysis by CTL793. The peptide also induced a CTL response in peripheral blood mononuclear cells (PBMC) of patient 793 and in two other melanoma patients...
2015: Molecular Therapy Oncolytics
Tek N Lamichhane, Aneeshkumar G Arimbasseri, Keshab Rijal, James R Iben, Fan Yan Wei, Kazuhito Tomizawa, Richard J Maraia
tRNA-isopentenyl transferases (IPTases) are highly conserved enzymes that form isopentenyl-N(6)-A37 (i6A37) on subsets of tRNAs, enhancing their translation activity. Nuclear-encoded IPTases modify select cytosolic (cy-) and mitochondrial (mt-) tRNAs. Mutation in human IPTase, TRIT1, causes disease phenotypes characteristic of mitochondrial translation deficiency due to mt-tRNA dysfunction. Deletion of the Schizosaccharomyces pombe IPTase (tit1-Δ) causes slow growth in glycerol, as well as in rapamycin, an inhibitor of TOR kinase that maintains metabolic homeostasis...
April 2016: RNA
P J Smaldino, D F Read, M Pratt-Hyatt, A K Hopper, D R Engelke
Mod5 is the yeast tRNA isopentenyl transferase, an enzyme that is conserved from bacteria to humans. Mod5 is primarily cytoplasmic where it modifies the A37 position of a few tRNAs, and the yeast enzyme has been shown capable of forming heritable, amyloid-like aggregates that confer a selective advantage in the presence of specific antifungal agents. A subpopulation of Mod5 is also found associated with nuclear tRNA genes, where it contributes tRNA-gene mediated (tgm) silencing of local transcription by RNA polymerase II...
February 1, 2015: Gene
John W Yarham, Tek N Lamichhane, Angela Pyle, Sandy Mattijssen, Enrico Baruffini, Francesco Bruni, Claudia Donnini, Alex Vassilev, Langping He, Emma L Blakely, Helen Griffin, Mauro Santibanez-Koref, Laurence A Bindoff, Ileana Ferrero, Patrick F Chinnery, Robert McFarland, Richard J Maraia, Robert W Taylor
Identifying the genetic basis for mitochondrial diseases is technically challenging given the size of the mitochondrial proteome and the heterogeneity of disease presentations. Using next-generation exome sequencing, we identified in a patient with severe combined mitochondrial respiratory chain defects and corresponding perturbation in mitochondrial protein synthesis, a homozygous p.Arg323Gln mutation in TRIT1. This gene encodes human tRNA isopentenyltransferase, which is responsible for i6A37 modification of the anticodon loops of a small subset of cytosolic and mitochondrial tRNAs...
June 2014: PLoS Genetics
Tek N Lamichhane, Sandy Mattijssen, Richard J Maraia
Human TRIT1 is a tRNA isopentenyltransferase (IPTase) homologue of Escherichia coli MiaA, Saccharomyces cerevisiae Mod5, Schizosaccharomyces pombe Tit1, and Caenorhabditis elegans GRO-1 that adds isopentenyl groups to adenosine 37 (i6A37) of substrate tRNAs. Prior studies indicate that i6A37 increases translation fidelity and efficiency in codon-specific ways. TRIT1 is a tumor suppressor whose mutant alleles are associated with cancer progression. We report the systematic identification of i6A37-containing tRNAs in a higher eukaryote, performed using small interfering RNA knockdown and other methods to examine TRIT1 activity in HeLa cells...
December 2013: Molecular and Cellular Biology
Shuqin Chen, Zhihua Zheng, Jianqing Tang, Xiandong Lin, Xiaojun Wang, Jianyin Lin
To explore the association of polymorphisms in the region of three neighboring genes TRIT1, MYCL1 and MFSD2A with risk and clinicopathological features of gastric cancer, 19 tagging SNPs in this region were genotyped using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry in a case-control study of 610 Chinese gastric cancer patients and 608 cancer-free controls. MFSD2A rs4233508 T>C CC genotype was associated with an increased risk of gastric cancer in younger patients and an increased risk of moderately/well-differentiated intestinal-type gastric cancer (adjusted odds ratio [OR], 1...
May 2013: Carcinogenesis
Noelia Fradejas, Bradley A Carlson, Eddy Rijntjes, Niels-Peter Becker, Ryuta Tobe, Ulrich Schweizer
Selenoproteins are proteins carrying the rare amino acid Sec (selenocysteine). Full expression of selenoproteins requires modification of tRNA([Ser]Sec), including N(6)-isopentenylation of base A(37). We show that Trit1 is a dimethylallyl:tRNA([Ser]Sec) transferase. Knockdown of Trit1 reduces expression of selenoproteins. Incubation of in vitro transcribed tRNA[Ser]Sec with recombinant Trit1 transfers [(14)C]dimethylallyl pyrophosphate to tRNA([Ser]Sec). 37A>G tRNA([Ser]Sec) is resistant to isopentenylation by Trit1...
March 1, 2013: Biochemical Journal
Tek N Lamichhane, Nathan H Blewett, Richard J Maraia
The N(6)-(isopentenyl)adenosine (i(6)A) modification of some tRNAs at position A37 is found in all kingdoms and facilitates codon-specific mRNA decoding, but occurs in different subsets of tRNAs in different species. Here we examine yeasts' tRNA isopentenyltransferases (i.e., dimethylallyltransferase, DMATase, members of the Δ(2)-isopentenylpyrophosphate transferase, IPPT superfamily) encoded by tit1(+) in Schizosaccharomyces pombe and MOD5 in Saccharomyces cerevisiae, whose homologs are Escherichia coli miaA, the human tumor suppressor TRIT1, and the Caenorhabditis elegans life-span gene product GRO-1...
October 2011: RNA
Monica Spinola, F Stefania Falvella, Antonella Galvan, Carmen Pignatiello, Vera P Leoni, Ugo Pastorino, Rita Paroni, Shuqing Chen, Vidar Skaug, Aage Haugen, Tommaso A Dragani
Linkage disequilibrium (LD) analysis to refine a region associated with lung cancer progression on chromosome 1p34 identified a 106 kb LD block that includes MYCL1, TRIT1 (tRNA isopentenyltransferase 1) and MFSD2 (major facilitator superfamily domain-containing 2). Case-only association study on SNPs mapping in TRIT1 and MFSD2 indicated that the rare Leu allele (frequency: 0.04) of the TRIT1 Phe202Leu variation predicts short survival as compared to the common Phe/Phe genotype (hazard ratio (HR)=1.7; 95% CI, 1...
March 2007: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Monica Spinola, Antonella Galvan, Carmen Pignatiello, Barbara Conti, Ugo Pastorino, Bjorn Nicander, Rita Paroni, Tommaso A Dragani
tRNA-isopentenyltransferase (tRNA-IPT) catalyses the addition of N6-isopentenyladenosine (i6A) on residue 37 of tRNA molecules that bind codons starting with uridine. Post-transcriptional modifications of tRNA molecules have been demonstrated to be essential in maintaining the correct reading frame of the translational machinery, thus improving fidelity and efficiency of protein synthesis. We show here that the human tRNA-isopentenyltransferase (TRIT1) gene encodes a complex pattern of mRNA variants through alternative splicing in both normal and tumor lung tissue and that the nonsense suppressor activity of tRNA-IPT is maintained only in the full-length mRNA isoform, as revealed by gene complementation in yeast...
August 18, 2005: Oncogene
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