title: Insights into the Initiation of Eukaryotic DNA Replication.
abstract: The initiation of DNA replication is a highly regulated event in eukaryotic cells to ensure that the entire genome is copied once and only once during S phase. The primary target of cellular regulation of eukaryotic DNA replication initiation is the assembly and activation of the replication fork helicase, the 11-subunit assembly that unwinds DNA at a replication fork. The replication fork helicase, called CMG for Cdc45-Mcm2-7, and GINS, assembles in S phase from the constituent Cdc45, Mcm2-7, and GINS proteins. The assembly and activation of the CMG replication fork helicase during S phase is governed by 2 S-phase specific kinases, CDK and DDK. CDK stimulates the interaction between Sld2, Sld3, and Dpb11, 3 initiation factors that are each required for the initiation of DNA replication. DDK, on the other hand, phosphorylates the Mcm2, Mcm4, and Mcm6 subunits of the Mcm2-7 complex. Sld3 recruits Cdc45 to Mcm2-7 in a manner that depends on DDK, and recent work suggests that Sld3 binds directly to Mcm2-7 and also to single-stranded DNA. Furthermore, recent work demonstrates that Sld3 and its human homolog Treslin substantially stimulate DDK phosphorylation of Mcm2. These data suggest that the initiation factor Sld3/Treslin coordinates the assembly and activation of the eukaryotic replication fork helicase by recruiting Cdc45 to Mcm2-7, stimulating DDK phosphorylation of Mcm2, and binding directly to single-stranded DNA as the origin is melted.
authors.affiliation: a Department of Biomedical Science; Florida State University College of Medicine ; Tallahassee , FL USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Bruck
authors.affiliation: a Department of Biomedical Science; Florida State University College of Medicine ; Tallahassee , FL USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Perez-Arnaiz
authors.affiliation: a Department of Biomedical Science; Florida State University College of Medicine ; Tallahassee , FL USA.
authors.forename: Max K
authors.initials: MK
authors.lastname: Colbert
authors.affiliation: a Department of Biomedical Science; Florida State University College of Medicine ; Tallahassee , FL USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kaplan
mesh_terms: D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000737:chemistry / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D064110:Minichromosome Maintenance Proteins / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016196:S Phase; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D029701:Saccharomyces cerevisiae Proteins; C547406:TICRR protein, human; D004247:DNA; D018844:Cyclin-Dependent Kinases; D064110:Minichromosome Maintenance Proteins
keywords: DNA replication; cancer; eukaryotic; helicase; initiation