An early warning system for DNA damage

On page 245, Stokes and Michael show that when DNA damage is present, not only is the replication checkpoint system activated, but an additional system directly notifies replication forks of the problem. Previous work had identified two mechanisms of damage-induced replication arrest, the checkpoint system and a general slowing of fork progression, but the new work uncovers a third mechanism.

After observing that alkylation-damaged DNA induces a checkpoint-independent block to undamaged DNA replication in Xenopus laevis extracts, the authors found that the damaged DNA activates a diffusible inhibitor that stops new replication forks from progressing. To stop fork progression, the inhibitor must be present during a short window of time early in the assembly of prereplication complexes. Paradoxically, its effect is to prevent the binding of the processivity factor PCNA, a much later event in fork assembly. The...