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Targeted Cancer Therapy via DNA Repair Discovery

Canadian scientists elucidate the mechanism of PNKP, a DNA repair enzyme, paving the way for innovations in targeted cancer therapies.

In normal cells damaged DNA can lead to the breakdown of chromosomes and, ultimately, cancers. On the other hand, damaging DNA in cancer cells is a useful way to eradicate them. A long-term goal of this research is to find ways to specifically block a DNA repair enzyme called polynucleotide kinase/phosphatase, or PNKP, from working in cancer cells as a possible new cancer therapy.  Mark Glover, from the University of Alberta (Canada), and colleagues have elucidated the mechanism of is PNKP.  Observing that the enzyme performs a chemical reaction on damaged DNA end, reversing the damage and releasing it so that the broken DNA strand can be welded together with the rest of the double helix, the team observed that the same enzyme and mechanism also works in cancer cells, essentially serving to protect them. The researchers are hopeful that their findings may lead to new approaches to specifically inhibit the PNKP enzyme in cancer cells.

Nicolas Coquelle, Zahra Havali-Shahriari, Nina Bernstein, Ruth Green, J. N. Mark Glover.  “Structural basis for the phosphatase activity of polynucleotide kinase/phosphatase on single- and double-stranded DNA substrates.”  PNAS 2011 108 (52) 21022-21027.