For decades, lithium chloride (LiCl) has been used as a treatment option for those living with bipolar disorder (BD). As a result, many studies have been conducted to examine its mode of action, toxicity, and downstream cellular responses. We know that LiCl is able to affect cell signaling and signaling transduction pathways through protein kinase C and glycogen synthase kinase-3, which are considered to be important in regulating gene expression at the translational level. However, additional downstream effects require further investigation, especially in translation pathway. In yeast, LiCl treatment affects the expression, and thus the activity, of PGM2, a phosphoglucomutase involved in sugar metabolism. Inhibition of PGM2 leads to the accumulation of intermediate metabolites of galactose metabolism causing cell toxicity. However, it is not fully understood how LiCl affects gene expression in this matter. In this study, we identified three genes, NAM7, PUS2, and RPL27B, which increase yeast LiCl sensitivity when deleted. We further demonstrate that NAM7, PUS2, and RPL27B influence translation and exert their activity through the 5′-Untranslated region (5′-UTR) of PGM2 mRNA in yeast.

Lithium chloride (LiCl) has been widely researched and utilized as a therapeutic option for bipolar disorder (BD). Several pathways, including cell signaling and signal transduction pathways in mammalian cells, are shown to be regulated by LiCl. LiCl can negatively control the expression and activity of PGM2, a phosphoglucomutase that influences sugar metabolism in yeast. In the presence of galactose, when yeast cells are challenged by LiCl, the phosphoglucomutase activity of PGM2p is decreased, causing an increase in the concentration of toxic galactose metabolism intermediates that result in cell sensitivity. Here, we report that the null yeast mutant strains DBP7∆ and YRF1-6∆ exhibit increased LiCl sensitivity on galactose-containing media. Additionally, we demonstrate that DBP7 and YRF1-6 modulate the translational level of PGM2 mRNA, and the observed alteration in translation seems to be associated with the 5′-untranslated region (UTR) of PGM2 mRNA. Furthermore, we observe that DBP7 and YRF1-6 influence, to varying degrees, the translation of other mRNAs that carry different 5′-UTR secondary structures.

Translation is a fundamental process in biology, and understanding its mechanisms is crucial to comprehending cellular functions and diseases. The regulation of this process is closely linked to the structure of mRNA, as these regions prove vital to modulating translation efficiency and control. Thus, identifying and investigating these fundamental factors that influence the processing and unwinding of structured mRNAs would be of interest due to the widespread impact in various fields of biology. To this end, we employed a computational approach and identified genes that may be involved in the translation of structured mRNAs. The approach is based on the enrichment of interactions and co-expression of genes with those that are known to influence translation and helicase activity. The in silico prediction found CAF20 and ECM32 to be highly ranked candidates that may play a role in unwinding mRNA. The activities of neither CAF20 nor ECM32 have previously been linked to the translation of PGM2 mRNA or other structured mRNAs. Our follow-up investigations with these two genes provided evidence of their participation in the translation of PGM2 mRNA and several other synthetic structured mRNAs.