Low Mcm2-7 levels (bottom) slow recovery from DNA replication inhibition.

Not all available origins of replication fire during a normal S-phase. But when replication is perturbed, otherwise dormant origins go to work, Woodward et al. show on page 673.

Cells initially respond to slowed replication by turning on the ATR-dependent checkpoint, which prevents other origins from firing and thus getting into trouble too. But if the cell decides it is time to recover from that checkpoint, the mechanism discovered by Woodward et al. may ensure that there are enough origins to get the job done.

The excess supply of origins arises from an excess of sites that have the minichromosome maintenance protein complexes, Mcm2-7. These complexes are loaded onto chromatin before S-phase and are required to license replication origins for use. However, the number of complexes loaded is much higher than the number normally used.

Working in Xenopus egg extract, Woodward et al. found that replication speed, origin spacing, and the slowing in response to the DNA polymerase inhibitor aphidicolin were normal with either the full complement of Mcm2-7 or a minimal amount.

When aphidicolin-treated cells were supplemented with caffeine, which inhibits the ATR-dependent DNA replication checkpoint, the cells' DNA replication was completely rescued if and only if there was the normal excess of Mcm2-7. The rescue correlated with a large increase in the number of forks fired.

In worms, reducing MCM7 levels with siRNA had little or no effect in the absence of replicative stress. But when DNA replication was inhibited, wild-type worms were fine but siRNA-treated worms died.

Woodward et al. think that a replication origin is actually a cluster of Mcm2-7–licensed sites spread around a primary origin. Once one of the Mcm2-7 sites fires, the ATR checkpoint protein blocks activation of neighboring complexes, but if it stalls, the checkpoint is relieved and other complexes can fire. Just how that system might work though is not yet clear. Given that not all origins in the genome fire at the same time, ATR must be able to exert local control.