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. 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). 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.

中文翻译：

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WRN 通过影响 HeLa 癌细胞核 mRNA 输出来调节翻译


沃纳综合征蛋白 (WRN) 属于解旋酶 RecQ 家族，其功能丧失会导致早衰疾病沃纳综合征 (WS)。我们之前证明，WRN 耗竭引起的早期细胞变化是转录后参与代谢途径的酶水平下降，这些代谢途径控制大分子合成并防止氧化应激。这种代谢转变可以被正常细胞耐受，但会导致快速生长的癌细胞线粒体功能障碍和急性氧化应激，从而抑制其增殖。为了确定这种代谢转变的机制，我们检查了 WRN 敲低后的整体蛋白质合成和 mRNA 核质分布。我们确定 HeLa 细胞中 WRN 的消耗会减弱整体蛋白质合成，但不会影响 mRNA 输出机制关键组件的水平。我们进一步观察到 WRN 耗尽会影响 mRNA 的核输出，并证明 WRN 与 mRNA 和核 RNA 输出因子 1 (NXF1) 相互作用。我们的研究结果表明，WRN 通过与 NXF1 输出受体的相互作用影响 mRNA 从细胞核的输出，从而影响细胞蛋白质稳态。总之，我们确定了 WRN 的新伙伴和新功能，这对癌细胞的增殖尤其重要。