PrefaceGenome maintenance is a constant problem in all cells and a coordinated response to DNA damage is required to maintain cellular viability and prevent disease. The ATR and ATM protein kinases are master regulators of the DNA damage response, signaling to control cell cycle transitions, DNA replication, DNA repair, and apoptosis. Recent studies have provided insights into the mechanisms controlling ATR activation, helped to explain the overlapping but non-redundant activities of ATR and ATM in DNA damage signaling, and clarified the critical functions of ATR in maintaining genome integrity. IntroductionAll cells have elaborate mechanisms to maintain their genomes. DNA can be damaged during replication, by reactive metabolic byproducts as well as environmental mutagens. Responding to and repairing DNA damage is critical for cell viability and disease prevention.The DNA damage response (DDR) is a signal transduction pathway that coordinates cell cycle transitions, DNA replication, DNA repair and apoptosis. The major regulators of the DDR are the phosphoinositide 3-kinase related protein kinases (PIKKs), including ataxia-telangiectasia mutated (ATM) and ATM and Rad3 related (ATR). ATM and ATR share many biochemical and functional similarities. Both are large kinases with significant sequence homology and a strong preference to phosphorylate serine or threonine residues that are followed by glutamine. Both target an overlapping set of substrates that promote cell cycle arrest and DNA repair. However, ATR is essential for the viability of replicating human and mouse cells, whereas ATM is not 1-3 . ATM functions in response to rare occurrences of double strand breaks. By contrast, ATR is activated during every S-phase to regulate the firing of replication origins, the repair of damaged replication forks and to prevent the premature onset of mitosis 4, 5 (Fig. 1).Mutations in ATM predispose carriers to cancer and are found in approximately 0.5-1% of the population 6, 7 . People with mutations in both alleles of ATM suffer from the neurodegenerative and cancer predisposition disorder ataxia-telangiectasia 8 . Mutations in ATR are rare and probably only compatible with viability when heterozygous or hypomorphic. While the only clear link between ATR gene mutation and disease is in a few patients with the rare Seckel syndrome (characterized by growth retardation and microcephaly) 9 , disruptions in the ATR pathway do cause genomic instability, and ATR is activated by most cancer chemotherapies. Furthermore, ATR signaling is a promising target for cancer drug development 10, 11 . This review will focus on ATR signaling in the DNA damage response, and compare and contrast it with the more specialized role of ATM. NIH Public Access Mechanisms of ATR ActivationThe broad functions and physiological importance of ATR derive in large part from recognizing the signals that lead to its activation versus that of ATM. Thus, we will address the mechanism of activation in some detail. Recognizing DNA damageAlthough ATR is activ...

Replication stress is a complex phenomenon which has serious implications for genome stability, cell survival, and human disease. Generation of aberrant replication fork structures containing single-stranded DNA activates the replication stress response, primarily mediated by the kinase ATM- and Rad3-related (ATR). ATR and its downstream effectors stabilize and help to restart stalled replication forks, avoiding the generation of DNA damage and genome instability. Understanding these pathways may be key to diagnosis and treatment of human diseases caused by defective responses to replication stress.

The p53 tumor suppressor protein is activated and phosphorylated on serine-15 in response to various DNA damaging agents. The gene product mutated in ataxia telangiectasia, ATM, acts upstream of p53 in a signal transduction pathway initiated by ionizing radiation. Immunoprecipitated ATM had intrinsic protein kinase activity and phosphorylated p53 on serine-15 in a manganese-dependent manner. Ionizing radiation, but not ultraviolet radiation, rapidly enhanced this p53-directed kinase activity of endogenous ATM. These observations, along with the fact that phosphorylation of p53 on serine-15 in response to ionizing radiation is reduced in ataxia telangiectasia cells, suggest that ATM is a protein kinase that phosphorylates p53 in vivo.