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Nucleic Acids Research Advance Access published online on January 20, 2009
Nucleic Acids Research, doi:10.1093/nar/gkn1086
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© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Structural Biology

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

Ammar A. E. Ali, Rachel M. Jukes, Laurence H. Pearl* and Antony W. Oliver*

Cancer Research UK DNA Repair Enzyme Group, Section of Structural Biology, The Institute of Cancer Research, London SW3 6JB, UK

*To whom correspondence should be addressed. Tel: 020 7153 5571; Fax: 020 7153 5457; Email: antony.oliver{at}icr.ac.uk Correspondence may also be addressed to Laurence H. Pearl. Tel: 020 7153 5443; Fax: 020 7153 5457; Email: laurence.pearl{at}icr.ac.uk

Received December 1, 2008. Revised December 22, 2008. Accepted December 24, 2008.

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.


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