Impairing the production of ribosomal RNA activates mammalian target of rapamycin complex 1 signalling and downstream translation factors

Li, Rui; Iadevaia, Valentina; Avérous, Julien; Taylor, Peter M.; Zhang, Ze; Proud, Christopher G.

doi:10.1093/nar/gku130

Cited by 41 publications

(29 citation statements)

References 62 publications

(110 reference statements)

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“…1A to D). This is in stark contrast to the results of other studies, where the knockdown of ribosome biogenesis proteins resulted in a concomitant reduction in cytosolic 80S ribosome levels (23,24). Our decreased ratio of polysomes/monoribosomes suggests a significant flaw in translation initiation following DHX33 knockdown (25,26).…”

Section: Dhx33contrasting

confidence: 99%

The DHX33 RNA Helicase Promotes mRNA Translation Initiation

Zhang

You

Wang

et al. 2015

Molecular and Cellular Biology

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b DEAD/DEAH box RNA helicases play essential roles in numerous RNA metabolic processes, such as mRNA translation, premRNA splicing, ribosome biogenesis, and double-stranded RNA sensing. Herein we show that a recently characterized DEAD/ DEAH box RNA helicase, DHX33, promotes mRNA translation initiation. We isolated intact DHX33 protein/RNA complexes in cells and identified several ribosomal proteins, translation factors, and mRNAs. Reduction of DHX33 protein levels markedly reduced polyribosome formation and caused the global inhibition of mRNA translation that was rescued with wild-type DHX33 but not helicase-defective DHX33. Moreover, we observed an accumulation of mRNA complexes with the 80S ribosome in the absence of functional DHX33, consistent with a stalling in initiation, and DHX33 more preferentially promoted structured mRNA translation. We conclude that DHX33 functions to promote elongation-competent 80S ribosome assembly at the late stage of mRNA translation initiation. Our results reveal a newly recognized function of DHX33 in mRNA translation initiation, further solidifying its central role in promoting cell growth and proliferation. Mammalian cells maintain tight control of global mRNA translation through the production of ribosomes (1, 2); deregulation in mRNA translation is frequently found in human diseases (3-6) and is regarded as one of the many factors contributing to cancer development (7-9).Most eukaryotic protein translation initiation occurs by an ordered assembly of a preinitiation complex on the 5= cap of mRNA (10). After mature mRNA is transported into the cytosol, the distinct 5= cap of mRNA is recognized and bound by a large protein complex comprising eukaryotic initiation factor 4E (eIF4E), eIF4A, and eIF4G as well as poly(A)-binding protein (PABP) (1,11,12). These factors coordinately prevent mRNA degradation while priming mRNAs for translation initiation.The initial step in mRNA translation involves formation of a ternary complex between eIF2-GTP, Met-tRNA interference, and small 40S ribosomal subunits. This process is stimulated by the translation initiation factors eIF1, eIF3, eIF4F, and eIF5 (13). This large complex, termed the 43S preinitiation complex, attaches to the activated 5= cap of mRNA. Bound RNA helicases are responsible for unwinding various secondary structures in mRNA as the complex scans along the mRNA from the 5= end to the 3= end until it finds the initiation codon. The 60S large ribosome subunit then joins with the 40S subunit to form an 80S ribosome under guidance from eIF5B-GTP (2, 13). eIF2-GTP and eIF5B-GTP are then hydrolyzed into their GDP forms to promote the assembly of the functional initiation complex (14). The detailed mechanism of how elongation-competent 80S ribosomes are assembled prior to initiation or what triggers initiation is not well understood.Mammalian mRNAs often contain highly structured untranslated regions (UTRs) at the 5= ends of their open reading frame sequences that must be unwound to allow ribosome recruitment and scanning. Not su...

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Section: Dhx33contrasting

confidence: 99%

The DHX33 RNA Helicase Promotes mRNA Translation Initiation

Zhang

You

Wang

et al. 2015

Molecular and Cellular Biology

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“…The rate of protein synthesis is directly linked to ribosome synthesis and rRNA transcription (28)(29)(30). Recently, it was shown that TERT associates with RNA polymerase I (pol I) under hyperproliferative conditions and thus stimulates ribosomal biogenesis (31).…”

Section: Introductionmentioning

confidence: 99%

Telomerase reverse transcriptase promotes cancer cell proliferation by augmenting tRNA expression

Khattar¹,

Kumar²,

Liu³

et al. 2016

Journal of Clinical Investigation

115

107

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“…Furthermore, enhancement of translational capacity depends on activation of the ERK pathway . However, enhancement of translational capacity alone makes a very small contribution to protein synthesis, whereas enhancement of translational activity depends on activation of the mTOR pathway . It has also been reported that ERK signaling could be supported by enhancement of translation activity via enhancement of translational capacity .…”

Section: Discussionmentioning

confidence: 99%

“…However, enhancement of translational capacity alone makes a very small contribution to protein synthesis, whereas enhancement of translational activity depends on activation of the mTOR pathway . It has also been reported that ERK signaling could be supported by enhancement of translation activity via enhancement of translational capacity . Therefore, activation of both the mTOR and ERK pathways would contribute to enhancement of translational capacity and translational activity, which is necessary for an effective increase in muscle protein synthesis.…”

Section: Discussionmentioning

confidence: 99%