Abstract
Complete genome duplication is essential for genetic homeostasis over successive cell generations. Higher eukaryotes possess a complex genome replication program that involves replicating the genome in units of individual chromatin domains with a reproducible order or timing. Two types of replication origin firing regulations ensure complete and well-timed domain-wise genome replication: (1) the timing of origin firing within a domain must be determined and (2) enough origins must fire with appropriate positioning in a short time window to avoid inter-origin gaps too large to be fully copied. Fundamental principles of eukaryotic origin firing are known. We here discuss advances in understanding the regulation of origin firing to control firing time. Work with yeasts suggests that eukaryotes utilise distinct molecular pathways to determine firing time of distinct sets of origins, depending on the specific requirements of the genomic regions to be replicated. Although the exact nature of the timing control processes varies between eukaryotes, conserved aspects exist: (1) the first step of origin firing, pre-initiation complex (pre-IC formation), is the regulated step, (2) many regulation pathways control the firing kinase Dbf4-dependent kinase, (3) Rif1 is a conserved mediator of late origin firing and (4) competition between origins for limiting firing factors contributes to firing timing. Characterization of the molecular timing control pathways will enable us to manipulate them to address the biological role of replication timing, for example, in cell differentiation and genome instability.
Highlights
Complete genome duplication is essential for genetic homeostasis over successive cell generations
The exact nature of the timing control processes varies between eukaryotes, conserved aspects exist: (1) the first step of origin firing, pre-initiation complex, is the regulated step, (2) many regulation pathways control the firing kinase Dbf4-dependent kinase, (3) Rif1 is a conserved mediator of late origin firing and (4) competition between origins for limiting firing factors contributes to firing timing
Rif1 localises in the vicinity of these origins and prevents DDK action, presumably by recruiting phosphatase 1 (PP1) [112,113] (Figure 4). It appears that yeast Rif1, Taz1 and PP1 constitute a set of versatile firing time regulators that integrate various signals to mediate late firing of different classes of origins
Summary
In most eukaryotes including metazoa the large-gap problem becomes aggravated by the fact that origin positions are not strictly determined by DNA sequence This generates an element of randomness in the location of origins and, a certain size distribution of small and large inter-origin distances [1]. Eukaryotic cells generate many more potential origins by origin licensing (discussed below) than fire in normal S phases [3,4,5,6,7,8] These are dormant origins that fire only if they have enough time, as shown in yeast and vertebrates [9,10,11]. This domain-wise replication may represent a way to make replication locally efficient within replication domains, despite low overall origin firing
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