Department of Biology, University of Florida, Gainesville, FL, USA.
Free Radic Biol Med. 2012 Mar 1;52(5):937-50. doi: 10.1016/j.freeradbiomed.2011.12.009. Epub 2011 Dec 23.
The nucleolus has recently emerged as a major coordinator of cellular stress responses by regulating the tumor suppressor p53. However, it is not known if the nucleolus regulates the cap 'n' collar (CnC) transcription factors SKN-1 and Nrf2, which activate conserved antioxidant and detoxification responses in C. elegans and mammals, respectively. A screen for negative regulators of detoxification genes in C. elegans identified the conserved WD40 repeat containing protein WDR-46. This protein is highly conserved with yeast UTP7, which functions in 18S rRNA processing and assembly of the 40S small ribosomal subunit. WDR-46 is expressed in the nucleoli of multiple tissues in C. elegans and is required for rRNA processing. Mutation or silencing of WDR-46 activates the single C. elegans CnC homologue SKN-1 and increases expression of its target genes. Depletion of wdr-46 reduces lifespan and stress resistance and SKN-1 partially compensates. Lastly, the C. elegans p53 homologue CEP-1 is partially required for activation of gst-4 when wdr-46 or other ribosome processing genes are silenced but not when translation initiation genes are silenced suggesting that disruptions to nucleolar function can activate SKN-1 by a mechanism that involves p53/cep-1 and is independent of protein translation.
核仁最近成为细胞应激反应的主要协调者，通过调节肿瘤抑制因子 p53。然而，目前尚不清楚核仁是否调节帽 'n' 领（CnC）转录因子 SKN-1 和 Nrf2，它们分别在秀丽隐杆线虫和哺乳动物中激活保守的抗氧化和解毒反应。在秀丽隐杆线虫中筛选解毒基因的负调节剂，鉴定出保守的 WD40 重复蛋白 WDR-46。这种蛋白与酵母 UTP7 高度保守，后者在 18S rRNA 加工和 40S 小核糖体亚基的组装中发挥作用。WDR-46 在秀丽隐杆线虫的多个组织的核仁中表达，并且是 rRNA 加工所必需的。WDR-46 的突变或沉默激活了秀丽隐杆线虫的单一 CnC 同源物 SKN-1，并增加了其靶基因的表达。wdr-46 的耗竭会降低寿命和应激抗性，而 SKN-1 则部分代偿。最后，当 WDR-46 或其他核糖体加工基因被沉默时，秀丽隐杆线虫的 p53 同源物 CEP-1 部分需要激活 gst-4，但当翻译起始基因被沉默时则不需要，这表明核仁功能的中断可以通过涉及 p53/cep-1 的机制激活 SKN-1，并且独立于蛋白质翻译。
