Wednesday, Feb 3, 2021

Molecular Biology of the Cell

Computational Modelling of Chromosome Re-Replication in Mutant Strains of Fission Yeast

Bela Novak, John J. Tyson

Typically cells replicate their genome only once per division cycle, but under some circumstances, both natural and unnatural, cells synthesize an overabundance of DNA, either in a disorganized fashion (‘over-replication’) or by a systematic doubling of chromosome number (‘endoreplication’). These variations on the theme of DNA replication and division have been studied in strains of fission yeast, Schizosaccharomyces pombe, carrying mutations that interfere with the function of mitotic cyclin-dependent kinase (Cdk1:Cdc13) without impeding the roles of DNA-replication loading-factor (Cdc18) and S-phase cyclin-dependent kinase (Cdk1:Cig2). Some of these mutations support endoreplication, and some over-replication. In this paper, we propose a dynamical model of the interactions among the proteins governing DNA replication and cell division in fission yeast. By computational simulations of the mathematical model, we account for the observed phenotypes of these re-replicating mutants, and by theoretical analysis of the dynamical system, we provide insight into the molecular distinctions between over-replicating and endoreplicating cells. In case of induced over- production of regulatory proteins, our model predicts that cells first switch from normal mitotic cell cycles to growth-controlled endoreplication, and ultimately to disorganized over-replication, parallel to the slow increase of protein to very high levels.