Initiating DNA synthesis: from recruiting to activating the MCM complex.
The exact duplication of a genome once per cell division is required of every proliferating cell. To achieve this goal, eukaryotes adopt a strategy that limits every replication origin to a single initiation event within a narrow window of the cell cycle by temporally separating the assembly of the pre-replication complex (pre-RC) from the initiation of DNA synthesis. A key component of the pre-RC is the hexameric MCM complex, which is also the presumed helicase of the growing forks. An elaborate mechanism recruits the MCM complex to replication origins, and a regulatory chain reaction converts the poised, but inactive, MCM complex into an enzymatically active helicase. A growing list of proteins, including Mcm10 and Cdt1, are involved in the recruitment process. Two protein kinases, the Cdc7-Dbf4 kinase (DDK) and the cyclin-dependent kinase (CDK), trigger a chain reaction that results in the phosphorylation of the MCM complex and finally in the initiation of DNA synthesis. A composite picture from recent studies suggests that DDK is recruited to the pre-RC during G1 phase but must wait until S phase to phosphorylate the MCM complex. CDK is required for the recruitment of Cdc45 and other downstream components of the elongation machinery.
Dept of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
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D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism / Q000648:ultrastructure; D002868:Chromosomal Proteins, Non-Histone; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis*; D004265:DNA Helicases / Q000378:metabolism*; D004261:DNA Replication / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D064168:Minichromosome Maintenance Complex Component 7; D064110:Minichromosome Maintenance Proteins; D009687:Nuclear Proteins / Q000378:metabolism; D051738:Origin Recognition Complex; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins
C102209:CDC45 protein, S cerevisiae; C066503:CDC6 protein, S cerevisiae; C467199:CDT1 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C076365:MCM10 protein, S cerevisiae; C489613:MCM10 protein, human; D009687:Nuclear Proteins; D051738:Origin Recognition Complex; D029701:Saccharomyces cerevisiae Proteins; D004247:DNA; D018844:Cyclin-Dependent Kinases; D004265:DNA Helicases; C491088:MCM7 protein, S cerevisiae; C101624:MCM7 protein, human; D064168:Minichromosome Maintenance Complex Component 7; D064110:Minichromosome Maintenance Proteins