Regulation of DNA replication by ATR: signaling in response to DNA intermediates.
The nuclear protein kinase ATR controls S-phase progression in response to DNA damage and replication fork stalling, including damage caused by ultraviolet irradiation, hyperoxia, and replication inhibitors like aphidicolin and hydroxyurea. ATR activation and substrate specificity require the presence of adapter and mediator molecules, ultimately resulting in the downstream inhibition of the S-phase kinases that function to initiate DNA replication at origins of replication. The data reviewed strongly support the hypothesis that ATR is activated in response to persistent RPA-bound single-stranded DNA, a common intermediate of unstressed and damaged DNA replication and metabolism.
Department of Genetics and Development, Hammer Health Sciences Center, Room 1620, Columbia University College of Physicians and Surgeons, 701 W. 168th Street, New York, NY 10032, USA. ds453@columbia.edu
David
D
Shechter
Vincenzo
V
Costanzo
Jean
J
Gautier
D000818:Animals; D016590:Aphidicolin / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D004247:DNA / Q000235:genetics*; D004249:DNA Damage; D004261:DNA Replication; D004277:DNA, Single-Stranded / Q000235:genetics; D006801:Humans; D006918:Hydroxyurea / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D016196:S Phase; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D015398:Signal Transduction; D014466:Ultraviolet Rays
D018797:Cell Cycle Proteins; D004277:DNA, Single-Stranded; D016590:Aphidicolin; D004247:DNA; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D006918:Hydroxyurea