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Specific Recognition of a Multiply Phosphorylated Motif in the DNA Repair Scaffold Xrcc1 by the Fha Domain of Human Pnk.

DOI: 10.1093/nar/gkn1086 DOI Help
PMID: 19155274 PMID Help

Authors: A. A. Ali (Cancer Research UK DNA Repair Enzyme Group) , R. M. Jukes (Cancer Research UK DNA Repair Enzyme Group) , L. Pearl (Cancer Research UK DNA Repair Enzyme Group) , Antony Oliver (Cancer Research UK DNA Repair Enzyme Group)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nucleic Acids Research , VOL 37 (5) , PAGES 1701-1712

State: Published (Approved)
Published: January 2009

Abstract: Short-patch repair of DNA single-strand breaks and gaps (SSB) is coordinated by XRCC1, a scaffold protein that recruits the DNA polymerase and DNA ligase required for filling and sealing the damaged strand. XRCC1 can also recruit end-processing enzymes, such as PNK (polynucleotide kinase 3?-phosphatase), Aprataxin and APLF (aprataxin/PNK-like factor), which ensure the availability of a free 3?-hydroxyl on one side of the gap, and a 5?-phosphate group on the other, for the polymerase and ligase reactions respectively. PNK binds to a phosphorylated segment of XRCC1 (between its two C-terminal BRCT domains) via its Forkhead-associated (FHA) domain. We show here, contrary to previous studies, that the FHA domain of PNK binds specifically, and with high affinity to a multiply phosphorylated motif in XRCC1 containing a pSer-pThr dipeptide, and forms a 2:1 PNK:XRCC1 complex. The high-resolution crystal structure of a PNK–FHA–XRCC1 phosphopeptide complex reveals the basis for this unusual bis-phosphopeptide recognition, which is probably a common feature of the known XRCC1-associating end-processing enzymes.

Journal Keywords: Binding; Calorimetry; DNA; DNA-Binding; Humans; Models; Molecular; Phosphopeptides; Phosphoric; Phosphorylation; Phosphotransferases; Protein; Tertiary; Sequence Deletion

Subject Areas: Biology and Bio-materials

Instruments: I04-Macromolecular Crystallography

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