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J Biol Chem, Vol. 274, Issue 34, 24176-24186, August 20, 1999

Molecular Cloning of the Human Gene, PNKP, Encoding a Polynucleotide Kinase 3'-Phosphatase and Evidence for Its Role in Repair of DNA Strand Breaks Caused by Oxidative Damage

Arshad Jilani^§, Dindial Ramotar^¶, Carolyn Slack^**, Colin Ong^§, Xiao Ming Yang^¶, Stephen W. Scherer^§§, and Dana D. Lasko^§

From the  Molecular Oncology Group, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, and Departments of ^§ Medicine and Human Genetics, and ^** Biology, McGill University, Montreal, Quebec H3T 1E2, ^¶ Research Centre, Hôpital Maisonneuve-Rosemont, Montreal, Quebec H1T 2M4, and the ^§§ Hospital for Sick Children, Department of Genetics, University of Toronto, Toronto, Ontario M5G 1X8, Canada

Mammalian polynucleotide kinases catalyze the 5'-phosphorylation of nucleic acids and can have associated 3'-phosphatase activity, predictive of an important function in DNA repair following ionizing radiation or oxidative damage. The sequences of three tryptic peptides from a bovine 60-kDa polypeptide that correlated with 5'-DNA kinase and 3'-phosphatase activities identified human and murine dbEST clones. The 57.1-kDa conceptual translation product of this gene, polynucleotide kinase 3'-phosphatase (PNKP), contained a putative ATP binding site and a potential 3'-phosphatase domain with similarity to L-2-haloacid dehalogenases. BLAST searches identified possible homologs in Caenorhabditis elegans, Schizosaccharomyces pombe, and Drosophila melanogaster. The gene was localized to chromosome 19q13.3-13.4. Northern analysis indicated a 2-kilobase mRNA in eight human tissues. A glutathione S-transferase-PNKP fusion protein displayed 5'-DNA kinase and 3'-phosphatase activities. PNKP is the first gene for a DNA-specific kinase from any organism. PNKP expression partially rescued the sensitivity to oxidative damaging agents of the Escherichia coli DNA repair-deficient xth nfo double mutant. PNKP gene function restored termini suitable for DNA polymerase, consistent with in vivo removal of 3'-phosphate groups, facilitating DNA repair.

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