title: CUL4B promotes replication licensing by up-regulating the CDK2-CDC6 cascade.
abstract: Cullin-RING ubiquitin ligases (CRLs) participate in the regulation of diverse cellular processes including cell cycle progression. Mutations in the X-linked CUL4B, a member of the cullin family, cause mental retardation and other developmental abnormalities in humans. Cells that are deficient in CUL4B are severely selected against in vivo in heterozygotes. Here we report a role of CUL4B in the regulation of replication licensing. Strikingly, CDC6, the licensing factor in replication, was positively regulated by CUL4B and contributed to the loading of MCM2 to chromatin. The positive regulation of CDC6 by CUL4B depends on CDK2, which phosphorylates CDC6, protecting it from APC(CDH1)-mediated degradation. Thus, aside being required for cell cycle reentry from quiescence, CDK2 also contributes to pre-replication complex assembly in G1 phase of cycling cells. Interestingly, the up-regulation of CDK2 by CUL4B is achieved via the repression of miR-372 and miR-373, which target CDK2. Our findings thus establish a CUL4B-CDK2-CDC6 cascade in the regulation of DNA replication licensing.
authors.affiliation: Ministry of Education Key Laboratory of Experimental Teratology and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Yongxin
authors.initials: Y
authors.lastname: Zou
authors.forename: Jun
authors.initials: J
authors.lastname: Mi
authors.forename: Wenxing
authors.initials: W
authors.lastname: Wang
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Lu
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.forename: Zhaojian
authors.initials: Z
authors.lastname: Liu
authors.forename: Huili
authors.initials: H
authors.lastname: Hu
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Gao
authors.forename: Baichun
authors.initials: B
authors.lastname: Jiang
authors.forename: Changshun
authors.initials: C
authors.lastname: Shao
authors.forename: Yaoqin
authors.initials: Y
authors.lastname: Gong
mesh_terms: D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication / Q000502:physiology*; D016193:G1 Phase / Q000502:physiology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D064111:Minichromosome Maintenance Complex Component 2; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D015703:Antigens, CD; C103706:CDC6 protein, human; C513384:CDH1 protein, human; C517832:CUL4B protein, human; D015820:Cadherins; D018797:Cell Cycle Proteins; D002843:Chromatin; D044842:Cullin Proteins; C561021:MIRN372 microRNA, human; C527114:MIRN373 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; C084859:MCM2 protein, human; D064111:Minichromosome Maintenance Complex Component 2