Chromosome replication

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Chromosome replication

Precise chromosomal DNA replication during S phase of the cell cycle is a crucial factor in the proper maintenance of the genome from generation to generation. The current "once-per-cell-cycle" model of eukaryotic chromosome duplication describes a highly coordinated process by which temporally regulated replicon clusters are sequentially activated and subsequently united to form two semi-conserved copies of the genome. Replicon clusters, or replication domains, are comprised of individual replication units that are synchronously activated at predetermined points during S phase. Bi-directional replication within each replicon is initiated at periodic AT-rich origins along each chromosome. Origins are not characterized by any specific nucleotide sequence, but rather the spatial arrangement of origin replication complexes (ORCs). Given the duration of the S phase and replication fork rate, adjacent origins must be appropriately spaced to ensure the complete replication of each replicon. Chromatin arrangement by the nuclear matrix may be the underpinning factor responsible for ORC positioning. The six subunit ORC binds to origins of replication in an ATP-dependent manner during late telophase and early G1. In yeast, each replication domain simply contains a single ORC binding site. However, more complex origins are characterized by an initiation zone where DNA synthesis may begin at numerous locations. A single round of DNA synthesis at each activated origin is achieved by "licensing" of the ORC. Replication initiation is limited to ORCs bound by the proper licensing proteins. These licensing proteins are removed upon commencement of replication. Inactivation of licensing machinery prior to S phase prevents re-licensing of origins and multiple rounds of replication within a domain. Progression through, and termination of, chromosome replication is controlled by S phase specific cyclins and CDKs which direct the timely phosphorylation of ORCs. Origin firing prompts the unwinding of DNA, displacement of histones and activation of replication forks. Different regions of chromosomal DNA replicate at characteristic periods during the S phase. Actively expressed euchromatin generally replicates during early S phase while highly-repetitive heterochromatin replicates later. During the "timing decision point" (TDP) in early G1, a replication timing plan is created. This plan confers the order of origin firing during S phase and suggests that timing is organized at the level of replication domains. Early- and late-replicating domains may be differentially regulated by unique initiation complexes. Although early- and late-firing origin complexes form at the same time during G1, different proteins are known to specifically bind to either class of origins. Differential regulation along with TDP origin distinction implies that origin modification during G1 is responsible for the delay of RC initiation. The varying structural properties of chromatin may also influence replication timing. Euchromatic regions of chromosomes are less compact and require less unwinding, thereby aiding the initiation of replication machinery. Moreover, high levels of transcription and the simultaneous binding of transcription factors help to loosen euchromatin. Conversely, the compact structure of heterochromatin could inhibit early replication initiation. Near the end of S phase, a checkpoint triggers the repair of damaged DNA and stalled replication forks. Entry into mitosis is prevented until the integrity of the entire genome is confirmed. Reassembly of the chromatin marks the completion of S phase ends and the beginning of G2.

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