Mathematical description of eukaryotic chromosome replication

Abstract

The DNA genome must be completely duplicated with exquisite accuracy before a cell divides. The origin of replication (the place replication starts) is a single unique DNA sequence in a bacterial genome (1). By contrast, eukaryotic chromosomes have numerous initiation start sites, but these sites are not defined by a particular sequence and they change location in each cell cycle (2, 3). How such a vital process as DNA replication is orchestrated in seemingly random fashion is a mystery. In PNAS, Kelly and Callegari (4) devise a simple mathematical model that largely describes global chromosome replication dynamics in the fission yeast Saccharomyces pombe , using extensive global datasets from Kaykov and Nurse (5) and from Daigaku et al. (6) of the Carr laboratory. Kelly and Callegari’s model requires few parameters and assumes that selection of initiation sites is stochastic. Their mathematical modeling depends on two main features: ( i ) AT-rich DNA to which the S. pombe origin recognition complex (ORC) binds, and ( ii ) DNA that is outside transcription units. The ability to describe the global landscape of replication over the S. pombe genome gives hope that the approach may apply to higher eukaryotes such as ourselves.\n\nThe quest to identify replication origin sequences in eukaryotes has a long and torturous history (3). Over three decades, many laboratories have tried to locate the elusive origin sequence in mammals, but this has often led to conflicting conclusions and hotly debated results. A main region of study was the 55-kb intergenic region between the dihydrofolate reductase (DHFR) and 2BE2121 loci of Chinese hamster ovary cells, a region that amplifies in response to methotrexate treatment (7). Dissection of this initiation region mostly resulted in less and less frequent initiations, although a few regions appeared to hold promise, including a region as small as 500 … \n\n[↵][1]1To whom correspondence should be addressed. Email: odonnel{at}rockefeller.edu.\n\n [1]: #xref-corresp-1-1