title: CRL4(WDR23)-Mediated SLBP Ubiquitylation Ensures Histone Supply during DNA Replication.
abstract: To maintain genome integrity and epigenetic information, mammalian cells must carefully coordinate the supply and deposition of histones during DNA replication. Here we report that the CUL4 E3 ubiquitin ligase complex CRL4(WDR23) directly regulates the stem-loop binding protein (SLBP), which orchestrates the life cycle of histone transcripts including their stability, maturation, and translation. Lack of CRL4(WDR23) activity is characterized by depletion of histones resulting in inhibited DNA replication and a severe slowdown of growth in human cells. Detailed analysis revealed that CRL4(WDR23) is required for efficient histone mRNA 3' end processing to produce mature histone mRNAs for translation. CRL4(WDR23) binds and ubiquitylates SLBP in vitro and in vivo, and this modification activates SLBP function in histone mRNA 3' end processing without affecting its protein levels. Together, these results establish a mechanism by which CUL4 regulates DNA replication and possible additional chromatin transactions by controlling the concerted expression of core histones.
authors.affiliation: Institute of Biochemistry, ETH Zurich, Otto-Stern-Weg 3, 8093 Zürich, Switzerland. Electronic address: mia.li@bc.biol.ethz.ch.
authors.forename: Mia M L
authors.initials: MM
authors.lastname: Brodersen
authors.affiliation: Institute of Biochemistry, ETH Zurich, Otto-Stern-Weg 3, 8093 Zürich, Switzerland.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Lampert
authors.affiliation: Institute of Biochemistry, ETH Zurich, Otto-Stern-Weg 3, 8093 Zürich, Switzerland.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Barnes
authors.affiliation: Institute of Biochemistry, ETH Zurich, Otto-Stern-Weg 3, 8093 Zürich, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Soste
authors.affiliation: Institute of Biochemistry, ETH Zurich, Otto-Stern-Weg 3, 8093 Zürich, Switzerland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Piwko
authors.affiliation: Institute of Biochemistry, ETH Zurich, Otto-Stern-Weg 3, 8093 Zürich, Switzerland. Electronic address: matthias.peter@bc.biol.ethz.ch.
authors.forename: Matthias
authors.initials: M
authors.lastname: Peter
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D004247:DNA / Q000096:biosynthesis* / Q000235:genetics; D004261:DNA Replication; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006367:HeLa Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D026721:RNA 3' End Processing; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016196:S Phase; D013997:Time Factors; D014162:Transfection; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D039221:mRNA Cleavage and Polyadenylation Factors / Q000235:genetics / Q000378:metabolism*; D053722:Receptors, Interleukin-17
chemical_list: D002352:Carrier Proteins; D004247:DNA; D006657:Histones; D009687:Nuclear Proteins; D012333:RNA, Messenger; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases; D039221:mRNA Cleavage and Polyadenylation Factors; C408922:IL17RB protein, human; D053722:Receptors, Interleukin-17; C092663:SLBP protein, human; C000620536:DDB1 and CUL4 associated factor 11, human