The DNA damage response kinase ATR is an essential regulator of genome integrity. TopBP1 functions as a general activator of ATR. We have recently shown that TopBP1 activates ATR through its regulatory subunit ATRIP and a PIKK regulatory domain (PRD) located adjacent to its kinase domain. This mechanism of ATR activation is conserved in the S. cerevisiae ortholog Mec1. ATR is a member of the PIKK family of protein kinases that includes ATM, DNA-PKcs, mTOR and SMG1. The PRD regulates the kinase activity of other PIKKs and may serve as a site of interaction between these kinase and their respective activators. Activation of ATR by TopBP1 is maximal at low substrate concentrations and declines exponentially as substrate concentration increases. These data are consistent with a model in which TopBP1 acts to alter the conformation of ATR-ATRIP to increase the ability of ATR to bind substrates. A further understanding of the mechanism of ATR activation will likely provide insights into the regulation of related PIKKs.
|Evidence ID||Analyze ID||Interactor||Interactor Systematic Name||Interactor||Interactor Systematic Name||Type||Assay||Annotation||Action||Modification||Phenotype||Source||Reference||Note|
|Evidence ID||Analyze ID||Gene||Gene Systematic Name||Gene Ontology Term||Gene Ontology Term ID||Qualifier||Aspect||Method||Evidence||Source||Assigned On||Annotation Extension||Reference|
|Evidence ID||Analyze ID||Gene||Gene Systematic Name||Phenotype||Experiment Type||Experiment Type Category||Mutant Information||Strain Background||Chemical||Details||Reference|
|Evidence ID||Analyze ID||Regulator||Regulator Systematic Name||Target||Target Systematic Name||Experiment||Assay||Construct||Conditions||Strain Background||Reference|