Cdc6 also contains an ATPase motif, and recruitment of yeast Cdc6 is dependent on ATP or non-hydrolyzable ATP analogs (Katie Hartland, Imperial Cancer Research Fund, London, UK). In the next step of pre-RC formation, ORC recruits the Cdc6 and Cdt1 proteins, which are themselves required for the assembly of Mcm2-Mcm7 onto DNA. Several ORC subunits have 'Walker' ATPase motifs, and Chesnokov reported that mutations in the Walker ATPase motif of Drosophila Orc1 left the ORC complex unable to bind specifically to origin DNA. Prasanth and Cong-Jun Li (National Institutes of Child Health and Human Development, Bethesda, USA) also showed cell-cycle-dependent disassembly of the ORC complex, suggesting that ORC is not simply a marker for replication origins but is likely to play a complex role in cell-cycle progression.Ī number of groups reported the analysis of nucleotide requirements during pre-RC assembly. Drosophila Orc6 is nevertheless required for ORC to bind specifically to replication origins. In both studies, Orc6 was seen to localize to the mid-body, the cytoplasmic bridge between two daughter cells, by telophase. Consistent with this, Supriya Prasanth (Cold Spring Harbor Laboratory, New York, USA) reported distinct subcellular localization patterns for human Orc6 and Orc2 and Igor Chesnokov (University of California, Berkeley, USA) reported that less than 50% of Drosophila Orc6 associates with the other ORC subunits. The reported results suggested that only a minority of Orc6 molecules is associated with this Orc1-Orc5 complex. Sanjay Vashee (Johns Hopkins University School of Medicine, Baltimore, USA) described the interactions between recombinant human ORC subunits, and proposed that Orc2, Orc3 and Orc4 form a core upon which Orc5 and then Orc1 can be assembled. Detailed characterization of ORC, which consists of six subunits, Orc1-Orc6, was reported by a number of groups. Loading of the proteins of the origin recognition complex (ORC) onto replication origins is the earliest known step in pre-RC assembly. One crucial step in this process is the loading of the minichromosome maintenance (Mcm) proteins Mcm2-Mcm7 onto DNA, which results in the origin becoming 'licensed' for only a single round of DNA replication. Previous work has revealed that chromosomal DNA replication is controlled by the sequential assembly of 'pre-replicative complex' (pre-RC) proteins onto specialized DNA sequences, the replication origins, early in the cell cycle.
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