Unwind and slow down: checkpoint activation by helicase and polymerase uncoupling.

Phosphoinositide 3-kinase related protein kinases (PIKK) including ataxia-telangiectasia mutated (ATM), DNAdependent protein kinase (DNA-PK), and ATM and Rad3-related (ATR) coordinate cellular responses to DNA damage. DNA-PK and ATM are primarily activated by double-strand breaks. The ATR kinase, in contrast, responds to numerous forms of genotoxic stress including intrastrand cross-links, oxidative damage, and polymerase toxins. At first glance, the disparate DNA structures that activate ATR impose a difficult biochemical challenge for damage sensing. However, recent data indicate that one DNA structure—single-stranded DNA (ssDNA) coated with a single-stranded DNA-binding protein (RPA)—is a common intermediate to activate ATR signaling in response to all of these genotoxic lesions. In this issue, Cimprich and colleagues (Byun et al. 2005) define how DNA damage and polymerase toxins use a common mechanism to generate the RPA–ssDNA needed to activate ATR. The method is the decoupling of helicase and polymerase activities at a replication fork.