Erik Boye and Beáta Grallert from the Department of Cell Biology at the Institute for Cancer Research published a Preview article in the March 6 issue of Cell (impact factor 30) entitled "In DNA Replication, the Early Bird Catches the Worm".
The authors summarize the article as follows:
The Preview highlights and discusses recent findings about how chromosomal replication start points (origins) are marked and utilized in eukaryotic cells. Setting up the chromosomes for initiation of replication is a complex, multistage process where most of the actors have been identified, but the regulatory mechanisms are, to a large extent, unknown. Most cancer cells are defective in regulating the start of chromosome replication, so this transition - from G1 phase to S phase - is considered crucial for cancer development. The regulation of the G1/S transition is the main interest of the authors' projects.
For correct execution of DNA replication it is essential to select and prepare the right number of replication origins. Then, the appropriate set of origins has to be activated for entry into and progression through S phase, to ensure that each region of the genome is replicated once and only once. It is unclear how origins of replication are recognized, but it is known to occur already in mitosis, at which time the six Origin Recognition Complex (ORC) proteins bind to chromatin (see Figure). Thereafter follows the addition of a long row of proteins and cofactors and enzymatic reactions, as indicated by the time-line and the staircase shown in the figure. At the top of the staircase is the door leading into DNA replication and S phase. In the previewed article Wu and Nurse (same issue of Cell) present data suggesting that ORC binding is crucial for determining whether and when a potential origin is used for replication initiation in the subsequent S phase. They show that overexpression of some of the later components in the sequence, such as Cdc45 and Dfp1-Hsk1 (see Figure), makes inefficient origins more efficient, suggesting that these factors are also important for regulation of origin usage. Interestingly, human Cdc7-Dbf4, the homologue of Hsk1-Dfp1, is expressed at an elevated level in a number of human cancers, highlighting the importance of the regulation of origin choice and usage in cancer development.
In DNA replication, the early bird catches the worm. (link to PubMed)
Boye E, Grallert B.
Cell. 2009 Mar 6;136(5):812-4.
Home page of Erik Boye's group: Yeast Cell Biology group