Proceedings of the National Academy of Sciences · 2008 · 124 citations · 28 references
Life SciencesGeneticsMolecular BiologyCell DivisionDna ReplicationMolecular Cell BiologyCell Cycle ControlCell Cycle SignalingCell-cycle CheckpointsCell-cycle RegulationReplication Checkpoint ControlReplication InitiationAtr ActivationAtr-mediated Checkpoint SignalingCell-cycle Checkpoint RegulationCheckpoint Control Of Replication InitiationCheckpoint Protein InteractionsReplication Checkpoint ActivationReplication Checkpoint SignalingYeast Cell Cycle Genetics
The Saccharomyces cerevisiae Mec1-Ddc2 checkpoint kinase complex (the ortholog to human ATR-ATRIP) is an essential regulator of genomic integrity. The S. cerevisiae BRCT repeat protein Dpb11 functions in the initiation of both DNA replication and cell cycle checkpoints. Here, we report a genetic and physical interaction between Dpb11 and Mec1-Ddc2. A C-terminal domain of Dpb11 is sufficient to associate with Mec1-Ddc2 and strongly stimulates the kinase activity of Mec1 in a Ddc2-dependent manner. Furthermore, Mec1 phosphorylates Dpb11 and thereby amplifies the stimulating effect of Dpb11 on Mec1-Ddc2 kinase activity. Thus, Dpb11 is a functional ortholog of human TopBP1, and the Mec1/ATR activation mechanism is conserved from yeast to humans.
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Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine.
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Medicine, Cancer Biology, Oncology +16
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Akiko Kumagai, Joon Lee, Hae Yong Yoo et al. · Cell · 2006 · 728 citations · Full text