ATR signaling at a glance.

The maintenance of genomic integrity is crucial for the survival of all organisms. In humans, compromised genomic integrity contributes to genetic disorders, aging and cancers. The task of safeguarding the genome is accomplished by the concerted action of a number of cellular processes, including DNA replication, DNA repair, senescence and apoptosis. Many, if not all, of these processes are regulated and coordinated by the DNA-damage checkpoint, which is a complex signaling network that is triggered by DNA damage or genomic instability. Two phospho inositide 3-kinase-like protein kinases (PIKKs) – ataxia telangiectasia mutated (ATM), and ATMand Rad3-related (ATR) – are master regulators of two major checkpoint pathways (Harper and Elledge, 2007). ATM is primarily activated by DNA double-strand breaks (DSBs), whereas ATR responds to a much broader spectrum of DNA damage, including DSBs and many types of DNA damage that interfere with DNA replication (Cimprich and Cortez, 2008; Zou, 2007). In contrast to ATM, ATR has a crucial role in stabilizing the genome during DNA replication and is essential for cell survival (Brown and Baltimore, 2003). Here, we summarize the recent findings on ATR signaling in four areas: sensing of DNA damage; activation of the ATR kinase; interplay between ATR and ATM; and phosphorylation of ATR substrates.