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ATR: An Essential Regulator of Genome Integrity Karlene A. Cimprich 1 and David Cortez 2 1  Department of Chemical and Systems Biology, Stanford University School of Medicine, Clark Center, 318 Campus Drive, W350B, Stanford, CA 94305-5441, [email protected], 650-498-4720 2  Department of  Biochemistry, Vanderbilt University School of Medicine, 613 Light Hall, 23rd @ Pierce Ave., Nashville, TN 37232, [email protected], 615-322-8547, website: http://www.mc.vanderbilt.edu/root/vumc.php? site=cortezlab Preface Genome 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. Introduction All 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 Author Manuscript  Nat Rev Mol Cell Biol. Author manuscript; available in PMC 2009 March 31. Published in final edited form as:  Nat Rev Mol Cell Biol . 2008 August ; 9(8): 616–627. doi:10.1038/nrm2450. N I  H P A A  u  t  h  o r  a n  u  s  c r i   p  t  N I  H - P A A  u  t  h  o r  a  u  s  c r i   p  t  N I  H - P A A  u  t  h  o r  a  u  s  c r i   p  t  
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