title: Post-transcriptional homeostasis and regulation of MCM2-7 in mammalian cells.
abstract: The MiniChromosome Maintenance 2-7 (MCM2-7) complex provides essential replicative helicase function. Insufficient MCMs impair the cell cycle and cause genomic instability (GIN), leading to cancer and developmental defects in mice. Remarkably, depletion or mutation of one Mcm can decrease all Mcm levels. Here, we use mice and cells bearing a GIN-causing hypomophic allele of Mcm4 (Chaos3), in conjunction with disruption alleles of other Mcms, to reveal two new mechanisms that regulate MCM protein levels and pre-RC formation. First, the Mcm4(Chaos3) allele, which disrupts MCM4:MCM6 interaction, triggers a Dicer1 and Drosha-dependent ≈ 40% reduction in Mcm2-7 mRNAs. The decreases in Mcm mRNAs coincide with up-regulation of the miR-34 family of microRNAs, which is known to be Trp53-regulated and target Mcms. Second, MCM3 acts as a negative regulator of the MCM2-7 helicase in vivo by complexing with MCM5 in a manner dependent upon a nuclear-export signal-like domain, blocking the recruitment of MCMs onto chromatin. Therefore, the stoichiometry of MCM components and their localization is controlled post-transcriptionally at both the mRNA and protein levels. Alterations to these pathways cause significant defects in cell growth reflected by disease phenotypes in mice.
authors.affiliation: Department of Biomedical Sciences and Center for Vertebrate Genomics, Cornell University College of Veterinary Medicine, Ithaca, NY 14853, USA.
authors.forename: Chen-Hua
authors.initials: CH
authors.lastname: Chuang
authors.forename: Dian
authors.initials: D
authors.lastname: Yang
authors.forename: Gongshi
authors.initials: G
authors.lastname: Bai
authors.forename: Amy
authors.initials: A
authors.lastname: Freeland
authors.forename: Steven C
authors.initials: SC
authors.lastname: Pruitt
authors.forename: John C
authors.initials: JC
authors.lastname: Schimenti
mesh_terms: D000818:Animals; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D006706:Homeostasis; D007930:Leucine / Q000032:analysis; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D064126:Minichromosome Maintenance Complex Component 3; D064148:Minichromosome Maintenance Complex Component 4; D064151:Minichromosome Maintenance Complex Component 6; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D054730:Protein Interaction Domains and Motifs; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; C551848:MIRN34a microRNA, mouse; C513269:Mcm3 protein, mouse; C489424:Mcm5 protein, mouse; D035683:MicroRNAs; D009687:Nuclear Proteins; D012333:RNA, Messenger; D004265:DNA Helicases; C516793:Mcm4 protein, mouse; C491205:Mcm6 protein, mouse; D064126:Minichromosome Maintenance Complex Component 3; D064148:Minichromosome Maintenance Complex Component 4; D064151:Minichromosome Maintenance Complex Component 6; D007930:Leucine