Abstract
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.
Highlights
Bipolar disorder (BD) is known to be associated with dysregulated signaling pathways
Since altered expression of PGM2 has been seen in the presence of LiCl [29], we examined to see if NAMSi7n,cPeUalSte2r,eodr eRxPpLr2e7ssBiownoouflPdGaMffe2cthPasGbMee2nexsepernesisniothneapt rtheseetnrcaensolfaLtiioCnl l[e2v9e],l.wPegemxa2mp iwneads ttaogsgeeed ifwNitAhMG7F,PPaUnSd2w, oersRtePrnL2b7lBotwaonuallydsaisffwecatsPdGoMne2teoxspereesifsiaonnyaotftthheetrthanreselagteionnesleavlteelr. ePdgmPG2Mp w2 eaxsptaregsgseiodn w(FitihguGrFeP3aAn)d
Yeast cells are sensitive to LiCl treatment due to the accumulation of the galactose intermediate metabolites including galactose-1-p [14,15]
Summary
Bipolar disorder (BD) is known to be associated with dysregulated signaling pathways. Sci. 2019, 20, x FOR PEER REVIEW in nonsense-mediated mRNA decay This gene codes for an RNA helicase, which binds to the small rlaibstolsyo, mRaPlLs2u7bBuennitc,ocdoenstrfoolrlinthgedleacragye froibroasosmpeaclifiscubsuunbiste,tbouftmitRiNs Anos.t kPnUoSw2nisifinivt oilsveindvionlvteRdNiAn mtraondsilfiactiaotniorneginultahteiomn.itIonchthoins dstruiadayn, dwealdsoempsoenusdtroauteritdhyaltadtieolnetoiofnsoomf yeenaustclgeeanrems NRNAMAs7., APUndS2l,aastnldy, RRPPLL2277BB iennccroedaseessfoserntshietivlaitrygeofriybeoassotmtoalLsiCubl.uFnoiltl,obwu-tuipt igsennoettikcninowvenstiifgiattiiosnins vsoulgvgeedstinintvroanlvselamtieonnt roefgtuhelasteiogne.neIns itnhyiseastsut dLyiC, wl seendseimtivointysttrhartoeutghhatthdeeilreetifofenctoof nyetraasnt sgleantieosnNofAPMG7M, P2.US2, and RPL27B increases sensitivity of yeast to LiCl. Follow-up genetic investigations suggest involvement of these g2.eRneessuinltyseast LiCl sensitivity through their effect on translation of PGM2. 4 when NAM7, PUS2, or RPL27B was deleted, whereas, for p281, there was no significant difference between the mutants and WT (Figure 5A,B) These results demonstrate that the tested genes do not appear to affect translation of mRNAs lacking structured regions and exert their activities on structured mRNAs. 2.4. RRPPLL2277BB ccoommppeennssaattee ffoorr iiss kknnoowwnn ttoo bbee iinnvvoollvveedd tthhee sseennssiittiivviittyy ooff IITTTT11Δ∆,, iinn nneeggaattiivvee rreegguullaattiioonn ooff ttrraannssllaattiioonn vviiaa DDHHHH11 ((RRNNAA hheelliiccaassee)) aanndd PPSSKK22 iiss iinnvvoollvveedd iinn ttrraannssllaattiioonn rreegguullaattiioonn ooff mmRRNNAAss wwiitthh uuOORRFFss.. eeIIFF22AA aanndd IITTTT11 ppaarrttiicciippaattee iinn ttrraannssllaattiioonn iinniittiiaattiioonn aanndd tteerrmmiinnaattiioonn sstteeppss,, rreessppeeccttiivveellyy
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