title: Clamping the Mec1/ATR checkpoint kinase into action.
abstract: The yeast checkpoint protein kinase Mec1, the ortholog of human ATR, is the essential upstream regulator of the cell cycle checkpoint in response to DNA damage and to stalling of DNA replication forks. The activity of Mec1/ATR is not directly regulated by the DNA substrates that signal checkpoint activation. Rather the signal appears to be transduced to Mec1 by factors that interact with the signaling DNA substrates. One of these factors, the DNA damage checkpoint clamp Rad17-Mec3-Ddc1 (human 9-1-1) is loaded onto gapped DNA resulting from the partial repair of DNA damage, and the Ddc1 subunit of this complex activates Mec1. In vertebrate cells, the TopBP1 protein (Cut5 in S. pombe and Dpb11 in S. cervisiae) that is also required for establishment of the replication fork, functions during replication fork dysfunction to activate ATR. Both mechanisms of activation generally upregulate the kinase activity towards all downstream targets.
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Majka
authors.forename: Peter M J
authors.initials: PM
authors.lastname: Burgers
mesh_terms: D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D004249:DNA Damage; D004261:DNA Replication / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C097185:DPB11 protein, S cerevisiae; C440013:Ddc1 protein, S cerevisiae; D047908:Intracellular Signaling Peptides and Proteins; C099938:MEC3 protein, S cerevisiae; D009687:Nuclear Proteins; D010750:Phosphoproteins; C501395:RAD17 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C088937:MEC1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases