ATM and ATR check in on origins: a dynamic model for origin selection and activation.
Initiation of DNA replication occurs at origins of replication, traditionally defined by specific sequence elements. Sequence-dependent initiation of replication is the rule in prokaryotes and in the yeast Saccharomyces cereviseae. However, sequence-dependent initiation does not appear to be absolutely required in metazoan eukaryotes. Origin firing is instead likely dependent on stochastic initiation from chromatin-defined loci, despite the demonstration of some specific origins. Based on some recent observations in Xenopus laevis egg extracts and in mammalian cell culture, we propose that timing of origin firing is dependent on feedback from active replicons. This dynamic regulation of replication is mediated by sensing of ongoing replication by the DNA-damage checkpoint kinases ATM and ATR, which in turn downregulate neighboring and distal origins and replicons by inhibition of the S-phase kinases Cdk2 and Cdc7 and by inhibition of the replicative Mcm helicase. Origin selection, activation, and replicon progression are therefore constrained in both space and time via feedback from the cell cycle and ongoing replication.
Shechter
David
D
Integrated Program in Cellular, Molecular, and Biophysical Studies, Department of Genetics and Development, Hammer Health Sciences Center, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA. ds453@columbia.edu
Gautier
Jean
J
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D018797:Cell Cycle Proteins / Q000502:physiology*; D000071877:Checkpoint Kinase 1; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology; D004247:DNA / Q000235:genetics / Q000502:physiology; D004249:DNA Damage; D004265:DNA Helicases / Q000502:physiology; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000502:physiology*; D015536:Down-Regulation; D029721:Drosophila Proteins / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D011494:Protein Kinases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D018741:Replication Origin / Q000235:genetics / Q000502:physiology*; D012093:Replicon / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D029867:Xenopus Proteins / Q000502:physiology*
D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D025521:Tumor Suppressor Proteins; D029867:Xenopus Proteins; D004247:DNA; D011494:Protein Kinases; C576898:Atr protein, Xenopus; C068619:CDC7 protein, human; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D000071877:Checkpoint Kinase 1; C444435:Mei-41 protein, Drosophila; D017346:Protein Serine-Threonine Kinases; D004265:DNA Helicases