ABSTRACT
Although ATM and ATR are related kinases and share many substrates, they are activated in response to different DNA structures at DSBs. ATR can be activated in response to a broader range of DNA damage that involves single-stranded (SS)–DS junctions. These structures most commonly arise when the replication fork encounters a DNA lesion due to the arrest of one polymerase while the other continues (see (Chen et al. 2012) and references therein), yet they can also be generated by nucleotide excision repair or during resection of a DSB. Replication blocking causes DNA polymerases to become uncoupled from the replicative helicases, resulting in the formation of single strand breaks. These are quickly coated by the ssDNA binding protein complex, Replication Protein A (RPA) (Flynn and Zou 2011). ATRIP is indispensable for ATR activation and stabilization, as it binds directly to RPA and thereby enables the ATR-ATRIP complex to localize to sites of damage (Zou and Elledge 2003) (Fig. 2A).
