A tale of two tails: Activation of DNA damage checkpoint kinase Mec1/ATR by the 9-1-1 clamp and by Dpb11/TopBP1

• Published in: DNA repair 2009-09, Vol.8 (9), p.996-1003
• Main Authors: Navadgi-Patil, Vasundhara M., Burgers, Peter M.
• Format: Article
• Language: English
• Subjects: Cell cycle; Cell Cycle Proteins - metabolism; Checkpoints; Clamp loaders; Clamps; DNA Damage; Enzyme Activation; Intracellular Signaling Peptides and Proteins - metabolism; Protein kinase; Protein-Serine-Threonine Kinases - metabolism; Saccharomyces cerevisiae - enzymology; Saccharomyces cerevisiae Proteins - metabolism
• ISSN: 1568-7864; 1568-7856
• DOI: 10.1016/j.dnarep.2009.03.011

The DNA damage and replication checkpoint kinase Mec1/ATR is a member of the PI3-kinase related kinases that function in response to various genotoxic stresses. The checkpoint clamp 9-1-1 (Rad9-Rad1-Hus1 in S. pombe and mammals; Ddc1-Rad17-Mec3 in S. cerevisiae) executes two distinct checkpoint functions. In S. cerevisiae, DNA-bound 9-1-1 directly activates Mec1 kinase activity, a function that has not been demonstrated in other organisms. A second, conserved activity of 9-1-1 is that of TopBP1/Cut5/Dpb11 recruitment to stalled replication sites; subsequent activation of Mec1/ATR is carried out by TopBP1/Cut5/Dpb11. Biochemical studies indicate that the mode of Mec1/ATR activation by S. cerevisiae 9-1-1 is analogous to activation by S. cerevisiae Dpb11 or by vertebrate TopBP1: activation is mediated by the intrinsically disordered C-terminal tail of each activator. The relative contributions made by multiple activators of Mec1/ATR are discussed.