WRN modulates translation by influencing nuclear mRNA export in HeLa cancer cells

Juan Manuel Iglesias-Pedraz,Lucio Comai,Jose Antonio Ayala Felix,Sergio Rafael Cruz-Visalaya,Diego Matia Fossatti-Jara,Valeria Valle-Riestra-Felice

doi:10.1186/s12860-020-00315-9

Abstract

BackgroundThe Werner syndrome protein (WRN) belongs to the RecQ family of helicases and its loss of function results in the premature aging disease Werner syndrome (WS). We previously demonstrated that an early cellular change induced by WRN depletion is a posttranscriptional decrease in the levels of enzymes involved in metabolic pathways that control macromolecular synthesis and protect from oxidative stress. This metabolic shift is tolerated by normal cells but causes mitochondria dysfunction and acute oxidative stress in rapidly growing cancer cells, thereby suppressing their proliferation.ResultsTo identify the mechanism underlying this metabolic shift, we examined global protein synthesis and mRNA nucleocytoplasmic distribution after WRN knockdown. We determined that WRN depletion in HeLa cells attenuates global protein synthesis without affecting the level of key components of the mRNA export machinery. We further observed that WRN depletion affects the nuclear export of mRNAs and demonstrated that WRN interacts with mRNA and the Nuclear RNA Export Factor 1 (NXF1).ConclusionsOur findings suggest that WRN influences the export of mRNAs from the nucleus through its interaction with the NXF1 export receptor thereby affecting cellular proteostasis. In summary, we identified a new partner and a novel function of WRN, which is especially important for the proliferation of cancer cells.

Highlights

The Werner syndrome protein (WRN) belongs to the RecQ family of helicases and its loss of function results in the premature aging disease Werner syndrome (WS)
This metabolic shift is tolerated by normal cells but causes acute oxidative stress overload in rapidly growing cancer cells, which suppresses their proliferation and further analysis suggested that the metabolic changes induced by WRN depletion are caused by attenuated translation [25]
WRN depletion results in decreased levels of de-novo protein synthesis Our previous work suggested that the metabolic changes induced by WRN depletion in cancer cells are caused by a posttranscriptional mechanism of deregulation [25], and we confirmed by room temp (RT)-Quantitative PCR (qPCR) that messenger Poly Adenylated RNA or mRNA (RNA) (mRNA) levels of the metabolic enzymes glucose 6-phosphate dehydrogenase (G6PD) and Isocitrate dehydrogenase (IDH1) are not downregulated after small hairpin complementary oligonucleotides of WRN gene (shWRN) induction in HeLa cancer cells (Supplementary Fig. 1A)

Summary

Introduction

The Werner syndrome protein (WRN) belongs to the RecQ family of helicases and its loss of function results in the premature aging disease Werner syndrome (WS). We previously demonstrated that an early cellular change induced by WRN depletion is a posttranscriptional decrease in the levels of enzymes involved in metabolic pathways that control macromolecular synthesis and protect from oxidative stress This metabolic shift is tolerated by normal cells but causes mitochondria dysfunction and acute oxidative stress in rapidly growing cancer cells, thereby suppressing their proliferation. Our data demonstrated that WRN depletion results in a significant decrease in the level of enzymes involved in metabolic pathways, including glucose 6-phosphate dehydrogenase (G6PD) that control macromolecular synthesis and protect cells from oxidative stress soon after WRN depletion [25] This metabolic shift is tolerated by normal cells but causes acute oxidative stress overload in rapidly growing cancer cells, which suppresses their proliferation and further analysis suggested that the metabolic changes induced by WRN depletion are caused by attenuated translation [25]

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Results

Discussion

Conclusion