title: Human nuclear Dicer restricts the deleterious accumulation of endogenous double-stranded RNA.
abstract: Dicer is a central enzymatic player in RNA-interference pathways that acts to regulate gene expression in nearly all eukaryotes. Although the cytoplasmic function of Dicer is well documented in mammals, its nuclear function remains obscure. Here we show that Dicer is present in both the nucleus and cytoplasm, and its nuclear levels are tightly regulated. Dicer interacts with RNA polymerase II (Pol II) at actively transcribed gene loci. Loss of Dicer causes the appearance of endogenous double-stranded RNA (dsRNA), which in turn leads to induction of the interferon-response pathway and consequent cell death. Our results suggest that Pol II-associated Dicer restricts endogenous dsRNA formation from overlapping noncoding-RNA transcription units. Failure to do so has catastrophic effects on cell function.
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: Eleanor
authors.initials: E
authors.lastname: White
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: Margarita
authors.initials: M
authors.lastname: Schlackow
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: Kinga
authors.initials: K
authors.lastname: Kamieniarz-Gdula
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: Nick J
authors.initials: NJ
authors.lastname: Proudfoot
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: Monika
authors.initials: M
authors.lastname: Gullerova
mesh_terms: D017209:Apoptosis; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000032:analysis / Q000737:chemistry / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006801:Humans; D007372:Interferons / Q000378:metabolism; D012319:RNA Polymerase II / Q000378:metabolism / Q000502:physiology; D012330:RNA, Double-Stranded / Q000378:metabolism*; D043244:Ribonuclease III / Q000032:analysis / Q000737:chemistry / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D002843:Chromatin; D012330:RNA, Double-Stranded; D007372:Interferons; D012319:RNA Polymerase II; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases