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Structural Basis of Mec1-Ddc2-RPA Assembly and Activation on Single-Stranded DNA at Sites of Damage.

Molecular cell | Oct 19, 2017

Mec1-Ddc2 (ATR-ATRIP) is a key DNA-damage-sensing kinase that is recruited through the single-stranded (ss) DNA-binding replication protein A (RPA) to initiate the DNA damage checkpoint response. Activation of ATR-ATRIP in the absence of DNA damage is lethal. Therefore, it is important that damage-specific recruitment precedes kinase activation, which is achieved at least in part by Mec1-Ddc2 homodimerization. Here, we report a structural, biochemical, and functional characterization of the yeast Mec1-Ddc2-RPA assembly. High-resolution co-crystal structures of Ddc2-Rfa1 and Ddc2-Rfa1-t11 (K45E mutant) N termini and of the Ddc2 coiled-coil domain (CCD) provide insight into Mec1-Ddc2 homodimerization and damage-site targeting. Based on our structural and functional findings, we present a Mec1-Ddc2-RPA-ssDNA composite structural model. By way of validation, we show that RPA-dependent recruitment of Mec1-Ddc2 is crucial for maintaining its homodimeric state at ssDNA and that Ddc2's recruitment domain and CCD are important for Mec1-dependent survival of UV-light-induced DNA damage.

Pubmed ID: 29033322 RIS Download

Mesh terms: Adaptor Proteins, Signal Transducing | Amino Acid Substitution | Cell Cycle Proteins | Crystallography, X-Ray | DNA, Fungal | DNA, Single-Stranded | Intracellular Signaling Peptides and Proteins | Models, Molecular | Mutation, Missense | Protein Structure, Quaternary | Protein Structure, Secondary | Protein-Serine-Threonine Kinases | Replication Protein A | Saccharomyces cerevisiae | Saccharomyces cerevisiae Proteins

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