Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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DNA Damage
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DNA Repair
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Enzyme Activation
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Humans
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Hydroxyurea / metabolism
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Intracellular Signaling Peptides and Proteins
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Nucleic Acid Synthesis Inhibitors / metabolism
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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Protein Serine-Threonine Kinases
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Saccharomyces cerevisiae / genetics
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Saccharomyces cerevisiae / metabolism*
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Saccharomyces cerevisiae Proteins / genetics
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Saccharomyces cerevisiae Proteins / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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Cell Cycle Proteins
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DPB11 protein, S cerevisiae
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Intracellular Signaling Peptides and Proteins
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LCD1 protein, S cerevisiae
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Nucleic Acid Synthesis Inhibitors
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Phosphoproteins
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Saccharomyces cerevisiae Proteins
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MEC1 protein, S cerevisiae
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Protein Serine-Threonine Kinases
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Hydroxyurea