Specific recognition of a multiply phosphorylated motif in the DNA repair scaffold XRCC1 by the FHA domain of human PNK

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'-pho...

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Bibliographic Details
Published in:	Nucleic acids research Vol. 37; no. 5; pp. 1701 - 1712
Main Authors:	Ali, Ammar A.E, Jukes, Rachel M, Pearl, Laurence H, Oliver, Antony W
Format:	Journal Article
Language:	English
Published:	England Oxford University Press 01-04-2009 Oxford Publishing Limited (England)
Subjects:	Amino Acid Motifs Binding Sites Calorimetry DNA Repair DNA Repair Enzymes - chemistry DNA Repair Enzymes - metabolism DNA-Binding Proteins - chemistry DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Humans Models, Molecular Phosphopeptides - chemistry Phosphopeptides - metabolism Phosphoric Monoester Hydrolases - chemistry Phosphoric Monoester Hydrolases - metabolism Phosphorylation Phosphotransferases (Alcohol Group Acceptor) - chemistry Phosphotransferases (Alcohol Group Acceptor) - metabolism Protein Binding Protein Structure, Tertiary Sequence Deletion Structural Biology X-ray Repair Cross Complementing Protein 1
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Summary:	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.
Bibliography:	ArticleID:gkn1086 ark:/67375/HXZ-QXZKB5KQ-8 istex:45BAC4026F033E9E07D0E380A73280C4E9F0EA2A ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0305-1048 1362-4962
DOI:	10.1093/nar/gkn1086