Fail-safe replication

How does the cell ensure that its DNA is replicated once and only once in every cell cycle? Replication takes place at many sites and must be regulated separately at each one. That's a tough job even in budding yeast, with ∼400 initiation sites, but a Herculean one in human cells, with as many as 100,000. Moreover, not all replication events are initiated at the same time.

Researchers in Joachim Li's lab (University of California, San Francisco, CA) are among those who have implicated three mechanisms in the prevention of reinitiation: phosphorylation of the origin recognition complex (ORC), downregulation of Cdc6 protein levels, and exclusion of the Mcm2–7 complex from the nucleus. Yet the authors were frustrated to find that when they disrupted any one of these mechanisms, the block to reinitiation...