Roles of Elongator Dependent tRNA Modification Pathways in Neurodegeneration and Cancer

Abstract

Transfer RNA (tRNA) is subject to a multitude of posttranscriptional modifications which can profoundly impact its functionality as the essential adaptor molecule in messenger RNA (mRNA) translation. Therefore, dynamic regulation of tRNA modification in response to environmental changes can tune the efficiency of gene expression in concert with the emerging epitranscriptomic mRNA regulators. Several of the tRNA modifications are required to prevent human diseases and are particularly important for proper development and generation of neurons. In addition to the positive role of different tRNA modifications in prevention of neurodegeneration, certain cancer types upregulate tRNA modification genes to sustain cancer cell gene expression and metastasis. Multiple associations of defects in genes encoding subunits of the tRNA modifier complex Elongator with human disease highlight the importance of proper anticodon wobble uridine modifications (xm⁵U₃₄) for health. Elongator functionality requires communication with accessory proteins and dynamic phosphorylation, providing regulatory control of its function. Here, we summarized recent insights into molecular functions of the complex and the role of Elongator dependent tRNA modification in human disease.

Keywords: Elongator; U34; cancer; diphthamide; epitranscriptomics; neurodegeneration; tRNA; tRNA modification; wobble uridine modifications.

Figure 1

Transfer RNA (tRNA) modifications associated with human disease. (A) Schematic representation of a cytoplasmic tRNA with disease linked modifications at indicated base positions. Modification genes linked to human diseases when mutated or upregulated are denoted (see Table 1 and references therein for details). (B) Overview of steps and genes involved in xm⁵U₃₄ synthesis. A broken line between U₃₄ and s²U₃₄ indicates the fact that several lines of evidence support preferential action of the thiolase on mcm⁵U₃₄ rather than unmodified U₃₄. Elongator specifies different subunits of the Elongator complex, whereas thiolase represents the complex composed of subunits CTU1 and CTU2. Abbreviations for U₃₄ modifications are according to the modomics database [14].

Figure 2

U₃₄ modifications in human diseases. Scheme showing the “Janus headed” nature of the Elongator complex that plays an important role in human health and disease. (Top) The pseudo-atomic model of the fully assembled Elongator complex is shown in cartoon and transparent surface representation (Elp1/orange, Elp2/yellow, Elp3/pink, Elp4/green, Elp5/blue, Elp6/brown). Additional regulatory factors (Kti11-Kti14, left) and subsequent modifications (right) are indicated and labeled (for further details, see text). (Bottom) The opposing roles of reduced or enhanced levels of cm⁵ modifications in neurodegenerative diseases and cancer are highlighted.