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Replication forks, chromatin loops and dormant replication origins

DOI: 10.1186/gb-2008-9-12-244

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Abstract:

It is critical that chromosomal DNA is precisely duplicated during S phase of the eukaryotic cell cycle, with no sections of DNA left unreplicated or replicated more than once. There is a considerable plasticity in this process because cells license many potential replication origins, of which only a small percentage are used in any one cell cycle, with the others remaining 'dormant'. This means that the usage of replication origins can change under different circumstances. For example, dormant replication origins can be activated when replication forks are inhibited to allow timely completion of the replication programme. A recent paper published in Nature by Courbet et al. [1] illustrates this plasticity of replication origin usage and shows that it is associated with longer-term changes to the organization of chromatin loops. The changes to chromatin organization can then directly affect the way that replication origins are used in subsequent cell cycles.The precise duplication of large eukaryotic chromosomes is a dauntingly complex task. For the DNA to be completely replicated, replication forks need to be initiated at thousands of replication origins scattered throughout the genome. This is made more difficult by the fact that replication forks can frequently stall, for example if they encounter damaged bases. It is also crucial that each replication origin does not fire more than once in a single S phase, as this would lead to local amplification of the DNA.During late mitosis and early G1, the cell licenses replication origins for use in the upcoming S phase by loading protein complexes composed of Mcm proteins (Mcm2-7 complexes) onto the origin DNA [2,3]. During S phase, Mcm2-7 at licensed origins can initiate replication forks. The Mcm2-7 complex moves with the replication forks, providing the essential DNA helicase activity that unwinds the DNA. This means that when an origin initiates a pair of forks, it is converted into the unlicensed state and cannot f

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