title: PKR is activated by cellular dsRNAs during mitosis and acts as a mitotic regulator.
abstract: dsRNA-dependent protein kinase R (PKR) is a ubiquitously expressed enzyme well known for its roles in immune response. Upon binding to viral dsRNA, PKR undergoes autophosphorylation, and the phosphorylated PKR (pPKR) regulates translation and multiple signaling pathways in infected cells. Here, we found that PKR is activated in uninfected cells, specifically during mitosis, by binding to dsRNAs formed by inverted Alu repeats (IRAlus). While PKR and IRAlu-containing RNAs are segregated in the cytosol and nucleus of interphase cells, respectively, they interact during mitosis when nuclear structure is disrupted. Once phosphorylated, PKR suppresses global translation by phosphorylating the α subunit of eukaryotic initiation factor 2 (eIF2α). In addition, pPKR acts as an upstream kinase for c-Jun N-terminal kinase and regulates the levels of multiple mitotic factors such as cyclins A and B and Polo-like kinase 1 and phosphorylation of histone H3. Disruption of PKR activation via RNAi or expression of a transdominant-negative mutant leads to misregulation of the mitotic factors, delay in mitotic progression, and defects in cytokinesis. Our study unveils a novel function of PKR and endogenous dsRNAs as signaling molecules during the mitosis of uninfected cells.
authors.affiliation: Center for RNA Research, Institute for Basic Science, Seoul 151-742, Korea; School of Biological Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Yoosik
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Center for RNA Research, Institute for Basic Science, Seoul 151-742, Korea; School of Biological Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Jung Hyun
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Center for RNA Research, Institute for Basic Science, Seoul 151-742, Korea; School of Biological Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Jong-Eun
authors.initials: JE
authors.lastname: Park
authors.affiliation: Center for RNA Research, Institute for Basic Science, Seoul 151-742, Korea; School of Biological Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Jun
authors.initials: J
authors.lastname: Cho
authors.affiliation: Center for RNA Research, Institute for Basic Science, Seoul 151-742, Korea; School of Biological Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Hyerim
authors.initials: H
authors.lastname: Yi
authors.affiliation: Center for RNA Research, Institute for Basic Science, Seoul 151-742, Korea; School of Biological Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: V Narry
authors.initials: VN
authors.lastname: Kim
mesh_terms: D020087:Alu Elements / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology; D059447:Cell Cycle Checkpoints / Q000235:genetics* / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis / Q000502:physiology*; D010766:Phosphorylation; D011485:Protein Binding; D012330:RNA, Double-Stranded / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D012330:RNA, Double-Stranded; D019892:eIF-2 Kinase
keywords: PKR; cell cycle; dsRNA; translation