title: Depletion of a nucleolar protein activates xenobiotic detoxification genes in Caenorhabditis elegans via Nrf /SKN-1 and p53/CEP-1.
abstract: 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.
authors.affiliation: Department of Biology, University of Florida, Gainesville, FL, USA.
authors.forename: Chi K
authors.initials: CK
authors.lastname: Leung
authors.forename: Hyacinth
authors.initials: H
authors.lastname: Empinado
authors.forename: Keith P
authors.initials: KP
authors.lastname: Choe
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism*; D002466:Cell Nucleolus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D051858:Forkhead Transcription Factors; D015870:Gene Expression; D005786:Gene Expression Regulation; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D008658:Inactivation, Metabolic / Q000235:genetics*; D008017:Life Expectancy; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism; D012335:RNA, Ribosomal / Q000378:metabolism; D013312:Stress, Physiological; D014157:Transcription Factors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015262:Xenobiotics / Q000378:metabolism*
chemical_list: C438244:CEP-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D009687:Nuclear Proteins; D012333:RNA, Messenger; D012335:RNA, Ribosomal; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C572490:WDR-46 protein, C elegans; D015262:Xenobiotics; C108831:daf-16 protein, C elegans; C073702:skn-1 protein, C elegans; D005982:Glutathione Transferase