title: DHX34 and NBAS form part of an autoregulatory NMD circuit that regulates endogenous RNA targets in human cells, zebrafish and Caenorhabditis elegans.
abstract: The nonsense-mediated mRNA decay (NMD) pathway selectively degrades mRNAs harboring premature termination codons but also regulates the abundance of cellular RNAs. We sought to identify transcripts that are regulated by two novel NMD factors, DHX34 and neuroblastoma amplified sequence (NBAS), which were identified in a genome-wide RNA interference screen in Caenorhabditis elegans and later shown to mediate NMD in vertebrates. We performed microarray expression profile analysis in human cells, zebrafish embryos and C. elegans that were individually depleted of these factors. Our analysis revealed that a significant proportion of genes are co-regulated by DHX34, NBAS and core NMD factors in these three organisms. Further analysis indicates that NMD modulates cellular stress response pathways and membrane trafficking across species. Interestingly, transcripts encoding different NMD factors were sensitive to DHX34 and NBAS depletion, suggesting that these factors participate in a conserved NMD negative feedback regulatory loop, as was recently described for core NMD factors. In summary, we find that DHX34 and NBAS act in concert with core NMD factors to co-regulate a large number of endogenous RNA targets. Furthermore, the conservation of a mechanism to tightly control NMD homeostasis across different species highlights the importance of the NMD response in the control of gene expression.
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
authors.forename: Dasa
authors.initials: D
authors.lastname: Longman
authors.forename: Nele
authors.initials: N
authors.lastname: Hug
authors.forename: Marianne
authors.initials: M
authors.lastname: Keith
authors.forename: Corina
authors.initials: C
authors.lastname: Anastasaki
authors.forename: E Elizabeth
authors.initials: EE
authors.lastname: Patton
authors.forename: Graeme
authors.initials: G
authors.lastname: Grimes
authors.forename: Javier F
authors.initials: JF
authors.lastname: Cáceres
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D019143:Evolution, Molecular; D020869:Gene Expression Profiling; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D059365:Nonsense Mediated mRNA Decay; D020365:RNA Helicases / Q000037:antagonists & inhibitors / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D015534:Trans-Activators / Q000502:physiology; D015027:Zebrafish / Q000235:genetics; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D029742:Caenorhabditis elegans Proteins; C117339:NBAS protein, human; C559843:NBAS protein, zebrafish; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D029961:Zebrafish Proteins; C584326:smgl-1 protein, C elegans; C584327:DHX34 protein, C elegans; C559844:DHX34 protein, human; C559842:DHX34 protein, zebrafish; D020365:RNA Helicases; C101828:UPF1 protein, human