Fewer forks make faster progress

Just as a large number of forks can inhibit someone unaccustomed to formal dining, an excess of replication forks can slow the rate of DNA synthesis, Zhong et al. reveal.

Cdc7 is the catalytic subunit of the Dbf4-dependent kinase, which initiates DNA replication by activating the DNA helicase complex MCM at replication origins. In response to DNA damage, the checkpoint protein Rad53 limits origin firing by inhibiting Cdc7. Rad53 also slows the progression of existing replication forks, but whether Cdc7 influences fork dynamics is unclear.

Zhong et al. found that, although cdc7 mutant yeast fired fewer origins than wild-type cells, their replication forks proceeded faster than normal from the origins that did initiate DNA synthesis, even in the presence of the DNA-damaging agent MMS. orc1 mutant yeast, which fail to recruit MCM to replication origins, also showed faster fork progression at the handful of origins that managed to fire, indicating that reduced levels of origin firing increase replication fork speed. mec1 mutants, on the other hand, initiated synthesis at more origins than wild-type cells and consequently showed decreased rates of replication fork progression.

Because there are fewer replication forks in yeast lacking Cdc7 or Orc1, MMS only weakly activated the DNA damage checkpoint and Rad53 in these cells, suggesting that reduced checkpoint activation is one reason these cells show rapid fork dynamics. But mec1 mutants have slow replication forks even though they lack the DNA damage checkpoint. This suggests that the amount of origin firing influences fork progression in other ways, too, possibly because individual forks must compete for limited amounts of essential replication factors or nucleotides.