Journal
NUCLEIC ACIDS RESEARCH
Volume 37, Issue 5, Pages 1701-1712Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkn1086
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Funding
- Cancer Research UK Programme [C302/A8265]
- Cancer Research UK Studentship
- MRC Research Studentship
- Cancer Research UK
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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 PNKFHAXRCC1 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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