WRN modulates translation by influencing nuclear mRNA export in HeLa cancer cells
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(2020) 21:71
BMC Molecular and Cell Biology
RESEARCH ARTICLE
Open Access
WRN modulates translation by influencing nuclear mRNA export in HeLa cancer cells Juan Manuel Iglesias-Pedraz1* , Diego Matia Fossatti-Jara1,2† , Valeria Valle-Riestra-Felice1†, Sergio Rafael Cruz-Visalaya1†, Jose Antonio Ayala Felix1† and Lucio Comai3
Abstract Background: 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. Results: To 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). Conclusions: Our 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. Keywords: Werner syndrome protein, mRNA export, NXF1 export receptor, Translation, Cancer, Senescence
Background Werner Syndrome (WS) is an autosomal recessive disorder of premature aging [1, 2]. WS is caused by mutations in a single gene located on chromosome 8 [3], which encodes a nuclear protein termed Werner syndrome protein (WRN) [4]. WRN has helicase and exonuclease activity [5–7], and is one of four human RecQ helicases that function as genome caretakers [8]. WS patients display a striking predisposition to the early development * Correspondence: [email protected] † Diego Matia Fossatti Jara, Valeria del Carmen Valle-Riestra Felice, Sergio Rafael Cruz Visalaya and Jose Antonio Ayala Felix contributed equally to this work. 1 Departamento de Investigación, Desarrollo e Innovación, Laboratorio de Genética Molecular y Bioquímica, Universidad Científica del Sur, Villa El Salvador, 15842 Lima, Peru Full list of author information is available at the end of the article
of a range of diseases, which are typically observed in older individuals during normal aging. These include atherosclerosis, osteoporosis, type II diabetes mellitus, and predisposition to several types of cancer, with a higher prevalence of mesenchymal malignancies (sarcomas) and relatively low incidence of carcinomas [2
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