title: Inositol hexakisphosphate kinase-1 mediates assembly/disassembly of the CRL4-signalosome complex to regulate DNA repair and cell death.
abstract: Inositol polyphosphates containing an energetic pyrophosphate bond are formed primarily by a family of three inositol hexakisphosphate (IP6) kinases (IP6K1-3). The Cullin-RING ubiquitin ligases (CRLs) regulate diverse biological processes through substrate ubiquitylation. CRL4, comprising the scaffold Cullin 4A/B, the E2-interacting Roc1/2, and the adaptor protein damage-specific DNA-binding protein 1, is activated by DNA damage. Basal CRL4 activity is inhibited by binding to the COP9 signalosome (CSN). UV radiation and other stressors dissociate the complex, leading to E3 ligase activation, but signaling events that trigger signalosome dissociation from CRL4 have been unclear. In the present study, we show that, under basal conditions, IP6K1 forms a ternary complex with CSN and CRL4 in which IP6K1 and CRL4 are inactive. UV dissociates IP6K1 to generate IP7, which then dissociates CSN-CRL4 to activate CRL4. Thus, IP6K1 is a novel CRL4 subunit that transduces UV signals to mediate disassembly of the CRL4-CSN complex, thereby regulating nucleotide excision repair and cell death.
authors.affiliation: The Solomon H. Snyder Department of Neuroscience.
authors.forename: Feng
authors.initials: F
authors.lastname: Rao
authors.affiliation: The Solomon H. Snyder Department of Neuroscience.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: The Solomon H. Snyder Department of Neuroscience.
authors.forename: A Basit
authors.initials: AB
authors.lastname: Khan
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Department of Pharmacology and Molecular Sciences, and.
authors.forename: Moataz M
authors.initials: MM
authors.lastname: Gadalla
authors.affiliation: The Solomon H. Snyder Department of Neuroscience.
authors.forename: Jiyoung Y
authors.initials: JY
authors.lastname: Cha
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Department of Pharmacology and Molecular Sciences, and.
authors.forename: Risheng
authors.initials: R
authors.lastname: Xu
authors.affiliation: The Solomon H. Snyder Department of Neuroscience.
authors.forename: Richa
authors.initials: R
authors.lastname: Tyagi
authors.affiliation: Department of Pharmacology and Molecular Sciences, and.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Dang
authors.affiliation: The Solomon H. Snyder Department of Neuroscience.
authors.forename: Anutosh
authors.initials: A
authors.lastname: Chakraborty
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Department of Pharmacology and Molecular Sciences, and Department of Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205 ssnyder@jhmi.edu.
authors.forename: Solomon H
authors.initials: SH
authors.lastname: Snyder
mesh_terms: D000818:Animals; D000075686:COP9 Signalosome Complex; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000528:radiation effects; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair / Q000528:radiation effects*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism*; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000528:radiation effects; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D002352:Carrier Proteins; D044842:Cullin Proteins; C485444:Ihpk1 protein, mouse; D046912:Multiprotein Complexes; C479529:RBX1 protein, human; C540494:RBX1 protein, mouse; C118307:RNF7 protein, human; D044767:Ubiquitin-Protein Ligases; D017856:Phosphotransferases (Phosphate Group Acceptor); C115134:IP6K1 protein, human; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex
keywords: Cullin Ring E3 ligases; DNA repair; UV radiation; inositol phosphates; signalosome