title: CUL-4 ubiquitin ligase maintains genome stability by restraining DNA-replication licensing.
abstract: To maintain genome stability, DNA replication is strictly regulated to occur only once per cell cycle. In eukaryotes, the presence of 'licensing proteins' at replication origins during the G1 cell-cycle phase allows the formation of the pre-replicative complex. The removal of licensing proteins from chromatin during the S phase ensures that origins fire only once per cell cycle. Here we show that the CUL-4 ubiquitin ligase temporally restricts DNA-replication licensing in Caenorhabditis elegans. Inactivation of CUL-4 causes massive DNA re-replication, producing cells with up to 100C DNA content. The C. elegans orthologue of the replication-licensing factor Cdt1 (refs 2, 3) is required for DNA replication. C. elegans CDT-1 is present in G1-phase nuclei but disappears as cells enter S phase. In cells lacking CUL-4, CDT-1 levels fail to decrease during S phase and instead remain constant in the re-replicating cells. Removal of one genomic copy of cdt-1 suppresses the cul-4 re-replication phenotype. We propose that CUL-4 prevents aberrant re-initiation of DNA replication, at least in part, by facilitating the degradation of CDT-1.
authors.affiliation: Department of Cellular Biology, University of Georgia, Athens, Georgia 30602, USA.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Zhong
authors.forename: Hui
authors.initials: H
authors.lastname: Feng
authors.forename: Fernando E
authors.initials: FE
authors.lastname: Santiago
authors.forename: Edward T
authors.initials: ET
authors.lastname: Kipreos
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle; D004261:DNA Replication; D018509:DNA, Helminth / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D016678:Genome; D008025:Ligases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D018510:RNA, Helminth / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
chemical_list: D029742:Caenorhabditis elegans Proteins; C475683:Cdt-1 protein, C elegans; C475682:Cul-4 protein, C elegans; D018509:DNA, Helminth; D018510:RNA, Helminth; D012333:RNA, Messenger; D044767:Ubiquitin-Protein Ligases; D008025:Ligases