Transfer RNA and human disease

Abstract

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.

Lack of tRNA-i6A modification causes mitochondrial-like metabolic deficiency in S. pombe by limiting activity of cytosolic tRNATyr, not mito-tRNA

“…Many nucleotides in tRNAs are post-transcriptionally modified and many affect tRNA stability or activity (Phizicky and Hopper 2010). A large number of mitochondrial disorders are due to mutations to mt-tRNAs encoded in the mt-DNA or to mt-tRNA modification or processing enzymes encoded in the nuclear DNA (Yarham et al 2010(Yarham et al , 2014Abbott et al 2014).…”

Four-leaf clover qRT-PCR: A convenient method for selective quantification of mature tRNA

“…However, alteration of tRNA levels because of mutations in tRNAs themselves or tRNA maturation enzymes has been reported to contribute to diseases. 4 In addition, global expression analyses using microarray system have revealed that tRNA abundance greatly varies among different human cells and tissues and suggested the translational regulation of mRNA expression by tRNA heterogeneity. [5][6][7] The variations of tRNA expression are also implicated in cancer and neurodegeneration.…”

tRN-A-RS Acts As Biomarker for Cancer and Other Diseases

“…Further structural and function analysis of ARS genes provide evidence that they have an impact on human life and contribute to the regulation and coordination processes in the mitochondria and nuclear genes simultaneously. Besides playing the major canonical role, their non-canonical pathways have a widespread impact; indeed, many researchers consider them as the hotspot of the regulation system [7][8][9][10][11][12][13]21,22]. Different factors are found to be associated with these gene mutations, like abnormal synthesis of enzyme, oxidative stress condition and other intrinsic and extrinsic causes.…”

“…Using Illumina/Solexa deep sequencing method, evidence of the presence of tRNA derived fragments in prostate cancer cells has emerged. Not the whole tRNAs, but 3´-tRNA fragments of pre-tRNA Ser , tRF-1001, dictate prostate cancer cell proliferation, but the precise mechanism of oncogenic transformation by tRNA fragments is yet to be discovered [8]. Recently it has been observed that small RNAs derived from tRNAs, namely, 5′ tRNA-halves, 5′tRHs, ~30-35 nts in length, are abundant in liver; increase significantly during chronic viral infection, and alter in abundance in liver cancer associated with these infections.…”

“…The cytoplasmic aminoacyl tRNA synthetase genes are designated with single letter amino acid code followed by RS; the mitochondrial counterpart has a '2' suffix. In human, the number of ARS/ARS2 genes is 37, distinguished into two distinct sets based on protein localization; 18 cytoplasmic ARS (including the bifunctional glutamyl-prolyl-tRNA synthetase, EPRS, in charge for aminoacylation of Glu and Pro, FARS needs two separate genes A and B); 17 mitochondrial ARS2 (QARS2 does not exist) and 2 dual-localized ARSs, GARS and KARS, in both cytoplasm and mitochondria [6][7][8]. The mitochondrial translation machinery is a combination of products of nuclear and mtDNA-encoded genes.…”