Universal Temporal Profile of Replication Origin Activation in Eukaryotes

Abstract

Although replication proteins are conserved among eukaryotes, the sequence requirements for replication initiation differ between species. In all species, however, replication origins fire asynchronously throughout S phase. The temporal program of origin firing is reproducible in cell populations but largely probabilistic at the single-cell level. The mechanisms and the significance of this program are unclear. Replication timing has been correlated with gene activity in metazoans but not in yeast. One potential role for a temporal regulation of origin firing is to minimize fluctuations in replication end time and avoid persistence of unreplicated DNA in mitosis. Here, we have extracted the population-averaged temporal profiles of replication initiation rates for S. cerevisiae, S. pombe, D. melanogaster, X. laevis and H. sapiens from genome-wide replication timing and DNA combing data. All the profiles have a strikingly similar shape, increasing during the first half of S phase then decreasing before its end. A previously proposed minimal model of stochastic initiation modulated by accumulation of a recyclable, limiting replication-fork factor and fork-promoted initiation of new origins, quantitatively described the observed profiles without requiring new implementations.The selective pressure for timely completion of genome replication and optimal usage of replication proteins that must be imported into the cell nucleus can explain the generic shape of the profiles. We have identified a universal behavior of eukaryotic replication initiation that transcends the mechanisms of origin specification. The population-averaged efficiency of replication origin usage changes during S phase in a strikingly similar manner in a highly diverse set of eukaryotes. The quantitative model previously proposed for origin activation in X. laevis can be generalized to explain this evolutionary conservation.

The spatial and temporal organization of origin firing during the S-phase of fission yeast

“…Such a high density of origin firing will contribute to the completion of genome replication. These results support the proposal that limiting replication factors are increasingly concentrated on the reducing amounts of unreplicated DNA to assist the completion of genome replication (Rhind 2006;Goldar et al 2009). Limiting factors previously proposed for replication include Cdc45, Sld2, Sld3, Dpb11, and the DDK protein kinase (Patel et al 2008;Wu and Nurse 2009;Mantiero et al 2011).…”

Random replication of the inactive X chromosome

“…3) is consistent with elevated origin initiation rates at later times during S phase, as observed in single-molecule analyses in frogs (Herrick et al 2000), human cells (Guilbaud et al 2011), and fission yeast (Patel et al 2006), and as predicted by mathematical models (Rhind 2006). Such an increase in firing probabilities as S phase progresseswhich at the extremity of very late S phase results in random replication-has been suggested to be a principle property of DNA replication in eukaryotes (Goldar et al 2009). …”

Model-based analysis of DNA replication profiles: predicting replication fork velocity and initiation rate by profiling free-cycling cells

“…Note that, while previous works have considered initiation rate that increases in time (Goldar et al 2009;Rhind et al 2010), here, we consider origin activation as a homogeneous Poisson process. This simplifies the analysis but does not affect our results or, in particular, our ability to identify changes in replicon length (see below).…”