The ATR barrier to replication-born DNA damage

Replication comes with a price. The molecular gymnastics that occur on DNA during its duplication frequently derive to a wide spectrum of abnormalities which are still far from understood. These are brought together under the unifying term "replicative stress" (RS) which likely stands for large and unprotected regions of single-stranded DNA (ssDNA). In addition to RS, recombinogenic stretches of ssDNA are also formed at resected DNA double strand breaks (DSBs). Both situations converge on a ssDNA intermediate, which is the triggering signal for a damage situation. The cellular response in both cases is coordinated by a phosphorylation-based signaling cascade that starts with the activation of the AIR (ATM and Rad3-related) kinase. Given that AIR is essential for replicating cells, understanding the consequences of a defective AIR response for a mammalian organism has been limited until recent years. We here discuss on the topic and review the findings that connect AIR to ageing and cancer. (C) 2010 Elsevier L.V. All rights reserved.