title: Structural basis for phosphorylation-dependent signaling in the DNA-damage response.
abstract: The response of eukaryotic cells to DNA damage requires a multitude of protein-protein interactions that mediate the ordered repair of the damage and the arrest of the cell cycle until repair is complete. Two conserved protein modules, BRCT and forkhead-associated (FHA) domains, play key roles in the DNA-damage response as recognition elements for nuclear Ser/Thr phosphorylation induced by DNA-damage-responsive kinases. BRCT domains, first identified at the C-terminus of BRCA1, often occur as multiple tandem repeats of individual BRCT modules. Our recent structural and functional work has revealed how BRCT repeats recognize phosphoserine protein targets. It has also revealed a secondary binding pocket at the interface between tandem repeats, which recognizes the amino-acid 3 residues C-terminal to the phosphoserine. We have also studied the molecular function of the FHA domain of the DNA repair enzyme, polynucleotide kinase (PNK). This domain interacts with threonine-phosphorylated XRCC1 and XRCC4, proteins responsible for the recruitment of PNK to sites of DNA-strand-break repair. Our studies have revealed a flexible mode of recognition that allows PNK to interact with numerous negatively charged substrates.
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: R Scott
authors.initials: RS
authors.lastname: Williams
authors.forename: Nina
authors.initials: N
authors.lastname: Bernstein
authors.forename: Megan S
authors.initials: MS
authors.lastname: Lee
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Rakovszky
authors.forename: Diana
authors.initials: D
authors.lastname: Cui
authors.forename: Ruth
authors.initials: R
authors.lastname: Green
authors.forename: Michael
authors.initials: M
authors.lastname: Weinfeld
authors.forename: J N Mark
authors.initials: JN
authors.lastname: Glover
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019313:BRCA1 Protein / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology; D004249:DNA Damage; D004260:DNA Repair; D051858:Forkhead Transcription Factors / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
chemical_list: D019313:BRCA1 Protein; D051858:Forkhead Transcription Factors