Transfer RNA and human disease

Department of Biochemistry, College of Medicine, University of Vermont Burlington, VT, USA
Frontiers in Genetics 06/2014; 5:158. DOI: 10.3389/fgene.2014.00158
Source: PubMed


Pathological mutations in tRNA genes and tRNA processing enzymes are numerous and result in very complicated clinical phenotypes. Mitochondrial tRNA (mt-tRNA) genes are "hotspots" for pathological mutations and over 200 mt-tRNA mutations have been linked to various disease states. Often these mutations prevent tRNA aminoacylation. Disrupting this primary function affects protein synthesis and the expression, folding, and function of oxidative phosphorylation enzymes. Mitochondrial tRNA mutations manifest in a wide panoply of diseases related to cellular energetics, including COX deficiency (cytochrome C oxidase), mitochondrial myopathy, MERRF (Myoclonic Epilepsy with Ragged Red Fibers), and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). Diseases caused by mt-tRNA mutations can also affect very specific tissue types, as in the case of neurosensory non-syndromic hearing loss and pigmentary retinopathy, diabetes mellitus, and hypertrophic cardiomyopathy. Importantly, mitochondrial heteroplasmy plays a role in disease severity and age of onset as well. Not surprisingly, mutations in enzymes that modify cytoplasmic and mitochondrial tRNAs are also linked to a diverse range of clinical phenotypes. In addition to compromised aminoacylation of the tRNAs, mutated modifying enzymes can also impact tRNA expression and abundance, tRNA modifications, tRNA folding, and even tRNA maturation (e.g., splicing). Some of these pathological mutations in tRNAs and processing enzymes are likely to affect non-canonical tRNA functions, and contribute to the diseases without significantly impacting on translation. This chapter will review recent literature on the relation of mitochondrial and cytoplasmic tRNA, and enzymes that process tRNAs, to human disease. We explore the mechanisms involved in the clinical presentation of these various diseases with an emphasis on neurological disease.

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Available from: Jamie A Abbott, Nov 21, 2014
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    • "This indicates that defects in the central nervous system are not simply consequences of protein synthesis and growth abnormalities. Moreover, additional reports have linked mutations in the tRNA biogenesis pathway with sterility phenotypes in humans, animals, and plants (Wang et al, 2012; Hussain et al, 2013; Lin et al, 2013; Pierce et al, 2013; Xie et al, 2013; Abbott et al, 2014). Less appreciated is the fact that tRNA genes are, together with rRNAs, the most transcribed genes in the genome and tRNAs represent major docking sites for RNA pol III (Dieci et al, 2007). "
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    ABSTRACT: RNase P is a conserved endonuclease that processes the 5' trailer of tRNA precursors. We have isolated mutations in Rpp30, a subunit of RNase P, and find that these induce complete sterility in Drosophila females. Here, we show that sterility is not due to a shortage of mature tRNAs, but that atrophied ovaries result from the activation of several DNA damage checkpoint proteins, including p53, Claspin, and Chk2. Indeed, we find that tRNA processing defects lead to increased replication stress and de-repression of transposable elements in mutant ovaries. We also report that transcription of major piRNA sources collapse in mutant germ cells and that this correlates with a decrease in heterochromatic H3K9me3 marks on the corresponding piRNA-producing loci. Our data thus link tRNA processing, DNA replication, and genome defense by small RNAs. This unexpected connection reveals constraints that could shape genome organization during evolution.
    The EMBO Journal 10/2015; DOI:10.15252/embj.201591006 · 10.43 Impact Factor
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    Frontiers in Genetics 09/2014; 5:336. DOI:10.3389/fgene.2014.00336
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    ABSTRACT: We are interested in identifying and characterizing loci of the human genome that harbor sequences resembling known mitochondrial and nuclear tRNAs. To this end, we used the known nuclear and mitochondrial tRNA genes (the "tRNA-Reference" set) to search for "tRNA-lookalikes" and found many such loci at different levels of sequence conservation. We find that the large majority of these tRNA-lookalikes resemble mitochondrial tRNAs and exhibit a skewed over-representation in favor of some mitochondrial anticodons. Our analysis shows that the tRNA-lookalikes have infiltrated specific chromosomes and are preferentially located in close proximity to known nuclear tRNAs (z-score ≤ -2.54, P-value ≤ 0.00394). Examination of the transcriptional potential of these tRNA-lookalike loci using public transcript annotations revealed that more than 20% of the lookalikes are transcribed as part of either known protein-coding pre-mRNAs, known lncRNAs, or known non-protein-coding RNAs, while public RNA-seq data perfectly agreed with the endpoints of tRNA-lookalikes. Interestingly, we found that tRNA-lookalikes are significantly depleted in known genetic variations associated with human health and disease whereas the known tRNAs are enriched in such variations. Lastly, a manual comparative analysis of the cloverleaf structure of several of the transcribed tRNA-lookalikes revealed no disruptive mutations suggesting the possibility that these loci give rise to functioning tRNA molecules.
    Frontiers in Genetics 10/2014; 5:344. DOI:10.3389/fgene.2014.00344
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