Structure and mechanism of the critical DNA repair enzyme, polynucleotide kinase/phosphatase (PNKP)

PNK is a key enzyme in the repair of DNA strand breaks, by both the non-homologous end joining, and base excision/single strand break repair pathways. We determined the crystal structure of the intact enzyme, revealing distinct kinase and phosphatase catalytic domains, and a distinct regulatory FHA domain. Our structure of the FHA domain bound to the scaffold protein XRCC4 reveals how PNK is recruited to sites of repair through phosphorylation-dependent interactions with key repair scaffold proteins. We have also characterized the distinct DNA substrate preferences for the phosphatase and kinase domains, which indicates that the two domains act independently. Together with our collaborator, Michael Weinfeld (Cross Cancer Institute), we plan to use this information to develop PNK inhibitors that could be lead compounds for new anti-cancer drug development.

Figure 1.
Weinfeld, M., Mani, R. S., Abdou, I., Aceytuno, R. D., Glover, J. N. M. (2011) Tidying up loose ends: the role of polynucleotide kinase/phosphatase in DNA strand break repair. Trends Biochem Sci. Epub ahead of print
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