Mitochondrial tRNA-lookalikes in nuclear chromosomes: Could they be functional?

Telonis, Aristeidis G.; Kirino, Yohei; Rigoutsos, Isidore

doi:10.1080/15476286.2015.1017239

Cited by 36 publications

(62 citation statements)

References 40 publications

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“…Studies of the tRFs' subcellular distributions are in their early stages (3). From this standpoint, the correlation of mitochondrial tRFs with processes that are not mitochondria-specific suggests possible biogenesis from either mitochondrial tRNAs that exit from the mitochondrion (50) or from the DNA of the mitochondrial "tRNA-lookalikes" that we reported in nuclear chromosomes (33). It is worth recalling that the mitochondria have established roles in cancer, at multiple levels between the genetic (48) and the metabolic processes (51), and that mitochondrial processes can signal and affect the nuclear genome's state (52).…”

Section: Discussionmentioning

confidence: 64%

“…The 22 mitochondrial tRNAs (3.5% of all tRNAs) are responsible for 6,031 (29%) of all distinct tRFs we find in TCGA. We note here that the human nuclear chromosomes are riddled with nuclear mitochondrial DNA segments (NUMT) as well as hundreds of tRNA-lookalikes (33). Thus, it is conceivable that the mitochondrial tRFs are not the exclusive product of the mitochondrial genome.…”

Section: Trf Lengths and Trna Cleavage Patterns Depend On The Genome mentioning

confidence: 87%

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tRNA Fragments Show Intertwining with mRNAs of Specific Repeat Content and Have Links to Disparities

et al. 2019

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tRNA-derived fragments (tRF) are a class of potent regulatory RNAs. We mined the datasets from The Cancer Genome Atlas (TCGA) representing 32 cancer types with a deterministic and exhaustive pipeline for tRNA fragments. We found that mitochondrial tRNAs contribute disproportionally more tRFs than nuclear tRNAs. Through integrative analyses, we uncovered a multitude of statistically significant and contextdependent associations between the identified tRFs and mRNAs. In many of the 32 cancer types, these associations involve mRNAs from developmental processes, receptor tyrosine kinase signaling, the proteasome, and metabolic pathways that include glycolysis, oxidative phosphorylation, and ATP synthesis. Even though the pathways are common to multiple cancers, the association of specific mRNAs with tRFs depends on and differs from cancer to cancer. The associations between tRFs and mRNAs extend to genomic properties as well; specifically, tRFs are positively correlated with shorter genes that have a higher density in repeats, such as ALUs, MIRs, and ERVLs. Conversely, tRFs are negatively correlated with longer genes that have a lower repeat density, suggesting a possible dichotomy between cell proliferation and differentiation. Analyses of bladder, lung, and kidney cancer data indicate that the tRF-mRNA wiring can also depend on a patient's sex. Sex-dependent associations involve cyclindependent kinases in bladder cancer, the MAPK signaling pathway in lung cancer, and purine metabolism in kidney cancer. Taken together, these findings suggest diverse and wide-ranging roles for tRFs and highlight the extensive interconnections of tRFs with key cellular processes and human genomic architecture.Significance: Across 32 TCGA cancer contexts, nuclear and mitochondrial tRNA fragments exhibit associations with mRNAs that belong to concrete pathways, encode proteins with particular destinations, have a biased repeat content, and are sex dependent.

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Section: Discussionmentioning

confidence: 64%

Section: Trf Lengths and Trna Cleavage Patterns Depend On The Genome mentioning

confidence: 87%

tRNA Fragments Show Intertwining with mRNAs of Specific Repeat Content and Have Links to Disparities

et al. 2019

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“…We use the terms “nuclear” and “mitochondrial” tRNAs to refer to the nuclearly-encoded and mitochondrially-encoded tRNAs, respectively. However, this distinction of the origin of the DNA precursor template may not be entirely accurate from a biological standpoint: as we recently reported [ 35 , 36 ], mitochondrially-encoded tRNAs have numerous lookalikes in the nuclear genome (see below and also Discussion).…”

Section: Resultsmentioning

confidence: 95%

Dissecting tRNA-derived fragment complexities using personalized transcriptomes reveals novel fragment classes and unexpected dependencies

et al. 2015

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We analyzed transcriptomic data from 452 healthy men and women representing five different human populations and two races, and, 311 breast cancer samples from The Cancer Genome Atlas. Our studies revealed numerous constitutive, distinct fragments with overlapping sequences and quantized lengths that persist across dozens of individuals and arise from the genomic loci of all nuclear and mitochondrial human transfer RNAs (tRNAs). Surprisingly, we discovered that the tRNA fragments' length, starting and ending points, and relative abundance depend on gender, population, race and also on amino acid identity, anticodon, genomic locus, tissue, disease, and disease subtype. Moreover, the length distribution of mitochondrially-encoded tRNAs differs from that of nuclearly-encoded tRNAs, and the specifics of these distributions depend on tissue. Notably, tRNA fragments from the same anticodon do not have correlated abundances. We also report on a novel category of tRNA fragments that significantly contribute to the differences we observe across tissues, genders, populations, and races: these fragments, referred to as i-tRFs, are abundant in human tissues, wholly internal to the respective mature tRNA, and can straddle the anticodon. HITS-CLIP data analysis revealed that tRNA fragments are loaded on Argonaute in a cell-dependent manner, suggesting cell-dependent functional roles through the RNA interference pathway. We validated experimentally two i-tRF molecules: the first was found in 21 of 22 tested breast tumor and adjacent normal samples and was differentially abundant between health and disease whereas the second was found in all eight tested breast cancer cell lines.

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“… 14 The human genome encodes >500 tRNA genes, 15 along with numerous tRNA-lookalikes resembling nuclear and mitochondrial tRNAs. 16 , 17 The multitude of tRNA genes in the genome, along with high stability, 18 places tRNAs among the most abundant RNA molecules in the cellular transcriptome. Because of their abundance and well-defined role in translation, RNA fragments derived from tRNAs, found in early NGS studies, were often disregarded as nonfunctional degradation products.…”

Section: Introductionmentioning

confidence: 99%

tRNA-Derived Short Non-coding RNA as Interacting Partners of Argonaute Proteins

Shigematsu

Kirino

2015

Gene�Regul Syst Bio

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The advent of next-generation sequencing technologies has not only accelerated findings on various novel non-coding RNA (ncRNA) species but also led to the revision of the biological significance and versatility of fundamental RNA species with canonical function, such as transfer RNAs (tRNAs). Although tRNAs are best known as adapter components of translational machinery, recent studies suggest that tRNAs are not always end products but can further serve as a source for short ncRNAs. In many organisms, various tRNA-derived ncRNA species are produced from mature tRNAs or their precursor transcripts as functional molecules involved in various biological processes beyond translation. In this review, we focus on the tRNA-derived ncRNAs associated with Argonaute proteins and summarize recent studies on their conceivable biogenesis factors and on their emerging roles in gene expression regulation as regulatory RNAs.

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Mitochondrial tRNA-lookalikes in nuclear chromosomes: Could they be functional?

Cited by 36 publications

References 40 publications

tRNA Fragments Show Intertwining with mRNAs of Specific Repeat Content and Have Links to Disparities

tRNA Fragments Show Intertwining with mRNAs of Specific Repeat Content and Have Links to Disparities

Dissecting tRNA-derived fragment complexities using personalized transcriptomes reveals novel fragment classes and unexpected dependencies

tRNA-Derived Short Non-coding RNA as Interacting Partners of Argonaute Proteins

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