Structural basis for phosphorylation-dependent signaling in the DNA-damage response.
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.
Williams
R Scott
RS
Department of Biochemistry, University of Alberta, Edmonton, AB, Canada.
Bernstein
Nina
N
Lee
Megan S
MS
Rakovszky
Melissa L
ML
Cui
Diana
D
Green
Ruth
R
Weinfeld
Michael
M
Glover
J N Mark
JN
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
D019313:BRCA1 Protein; D051858:Forkhead Transcription Factors