The cytoplasmic and nuclear populations of the eukaryote tRNA-isopentenyl transferase have distinct functions with implications in human cancer

Abstract

Mod5 is the yeast tRNA isopentenyl transferase, an enzyme that is conserved from bacteria to humans. Mod5 is primarily cytoplasmic where it modifies the A37 position of a few tRNAs, and the yeast enzyme has been shown capable of forming heritable, amyloid-like aggregates that confer a selective advantage in the presence of specific antifungal agents. A subpopulation of Mod5 is also found associated with nuclear tRNA genes, where it contributes tRNA-gene mediated (tgm) silencing of local transcription by RNA polymerase II. The tgm-silencing function of Mod5 has been observed in yeast and a Mod5-deletion in yeast can be complemented by the plant and human tRNA isopentenyl transferases, but not the bacterial enzymes, possibly due to the lack of an extended C-terminal domain found in eukaryotes. In light of this additional nuclear role for Mod5 we discuss the proposed role of the human homologue of Mod5, TRIT1, as a tumor suppressor protein.

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

“…While the tRNA isopentenyltransferases (IPTases) that create i6A37 are conserved, they are nonessential in bacteria and yeasts (Smaldino et al 2015). Yeast lacking IPTase grow normally in standard media (Laten et al 1978;Janner et al 1980;Laten 1984;Dihanich et al 1987).…”

Systemic disruption of the homeostasis of transfer RNA isopentenyltransferase causes growth and development abnormalities in Bombyx mori

“…To become fully active, tRNA is subjected to extensive post-transcriptional alterations, and tRNA modification genes account for 1-10% of the genes in a given genome (El Yacoubi et al, 2012). The effects of these numerous post-transcriptional modifications include changes in tRNA stability, translation efficiency and translation fidelity (Urbonavičius et al, 2001;Phizicky and Hopper, 2010;Smaldino et al, 2015). Hypomodification can change the charging level of a tRNA, in turn resulting in translational slowdown, disrupting protein homeostasis and reducing cellular fitness (Koh and Sarin, 2018).…”

“…tRNA without isopentenylation modification severely inhibited translation and growth rates, and the gene responsible for this modification was shown to be MiaA (Diaz et al, 1987). The nuclear function of Mod5 and Trit1 was distinct from their tRNA-isopentenylation activity, and they were shown to contribute to tRNA-gene-mediated silencing of local transcription by RNA polymerase II (Pratt-Hyatt et al, 2013;Smaldino et al, 2015). The mod5-1 homozygotes sporulated poorly, but growth rate of the heterozygote was unaffected (Laten et al, 1978;Schweizer et al, 2017).…”

Aggregation of Mod5 is affected by tRNA binding with implications for tRNA gene‐mediated silencing

“…tRNA isopentenyl transferases are highly conserved enzymes that transfer an isopentenyl group from dimethylallylpyrophosphate (DMAPP) to the N6 position of A37, adjacent to the anticodon .The Saccharomyces cerevisiae enzyme, Mod5, resides primarily in the cytoplasm where it modifies mitochondrial and cytoplasmic tRNAs . Mod5 modifies a subset of tRNAs with specific sequence requirements (AAA) surrounding the target nucleotide at A37 .…”

“…A small fraction of the enzyme also resides in the nucleus , where it is required for a form of transcriptional silencing, termed tRNA gene‐mediated (tgm) silencing . tgm silencing was originally observed in budding yeast as antagonizing pol II gene promoters adjacent to tRNA genes .…”