Modify or die?--RNA modification defects in metazoans

Abstract

Chemical RNA modifications are present in all kingdoms of life and many of these post-transcriptional modifications are conserved throughout evolution. However, most of the research has been performed on single cell organisms, whereas little is known about how RNA modifications contribute to the development of metazoans. In recent years, the identification of RNA modification genes in genome wide association studies (GWAS) has sparked new interest in previously neglected genes. In this review, we summarize recent findings that connect RNA modification defects and phenotypes in higher eukaryotes. Furthermore, we discuss the implications of aberrant tRNA modification in various human diseases including metabolic defects, mitochondrial dysfunctions, neurological disorders, and cancer. As the molecular mechanisms of these diseases are being elucidated, we will gain first insights into the functions of RNA modifications in higher eukaryotes and finally understand their roles during development.

Keywords: RNA modification; cancer; mRNA; metabolism; methylation; mitochondria; neuropathy; rRNA; tRNA; translation.

Figure 1.

tRNA modification defects and phenotypes in higher eukaryotes. Schematic representation of a tRNA. Modified nucleosides that have been linked to phenotypes in higher eukaryotes are indicated as red circles. The color inside the circle denotes the type of defect observed. Chemical modifications and their causative genes (in brackets) are linked to the respective nucleoside. Gray or black residues depict nucleosides that are either unmodified or not linked to phenotypes. Abbreviations of the nucleosides follow the nomenclature of Modomics (http://modomics.genesilico.pl/).

Figure 2.

RNA modification genes associated with human malignancies. Schematic representation of various cancers for which increase (red) or decrease (blue) of tRNA modification gene copy number, or expression level, has been reported. (Source: Cosmic and Oncomine).

Figure 3.

Models of how RNA modification defects cause phenotypes. Comparison of different scenarios in an unperturbed (left) and pathogenic (right) situation. (A) A metabolic pathway is blocked, leading to the absence of modified RNA (indicated by an asterisk) and the build up of a different metabolite (in this case Z). (B) Ribosomes (orange) translating an mRNA, which contains a region that is difficult to translate (red box). In the pathogenic situation translation is perturbed, leading to a lower amount of protein. (C) As in (B). Perturbed translation prevents the folding of some proteins into their native state resulting in perturbed protein homeostasis. (D) tRNA fragments cause a slowdown of translation.