Deciphering DNA replication dynamics in eukaryotic cell populations in relation with their averaged chromatin conformations.

We propose a non-local model of DNA replication that takes into account the observed uncertainty on the position and time of replication initiation in eukaryote cell populations. By picturing replication initiation as a two-state system and considering all possible transition configurations, and by taking into account the chromatin's fractal dimension, we derive an analytical expression for the rate of replication initiation. This model predicts with no free parameter the temporal profiles of initiation rate, replication fork density and fraction of replicated DNA, in quantitative agreement with corresponding experimental data from both S. cerevisiae and human cells and provides a quantitative estimate of initiation site redundancy. This study shows that, to a large extent, the program that regulates the dynamics of eukaryotic DNA replication is a collective phenomenon that emerges from the stochastic nature of replication origins initiation.

A novel Hansenula polymorpha transcriptional factor HpHAP4-B, able to functionally replace the S. cerevisiae HAP4 gene, contains an additional bZip motif.

The transcriptional regulator HAP4, whose expression is induced on respiratory substrates, has been shown to be involved in the balance between fermentation and respiration in Saccharomyces cerevisiae. We have previously identified a HAP4 orthologue in the yeast Hansenula polymorpha, called HpHAP4-A, which, despite its very limited sequence conservation (a 16 amino acid N-terminal motif), is fully functional in S. cerevisiae. Based on the same N-terminal motif, a second gene has now been identified in the same organism. It was shown to contain an additional cis-binding motif of the bZip type. We report on the cloning, heterologous expression and analysis in S. cerevisiae of this novel ScHAP4 orthologue. From these experiments we could conclude that, as with HpHAP4-A, the novel orthologue, designated HpHAP4-B, could functionally replace the S. cerevisiae gene but to a lesser extent. The relationship between the presence of the additional cis-binding motif and the weaker potential as a HAP4 functional homologue is discussed.