A 3'-5' exonuclease in human leukemia cells: implications for resistance to 1-beta -D-arabinofuranosylcytosine and 9-beta -D-arabinofuranosyl-2-fluoroadenine 5'-monophosphate.

V Skalski, K R Brown, B Y Choi, Z Y Lin, S Chen

Journal: The Journal of biological chemistry 2000;275(33):25814-9

PMID: 10833512

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Abstract

A 3'-5' exonuclease that excises the nucleotide analogs 1-beta-d-arabinofuranosylcytosine monophosphate and 9-beta-d-arabinofuranosyl-2-fluoroadenine 5'-monophosphate incorporated at 3' ends of DNA was purified from the nuclei of: 1) primary human chronic lymphocytic leukemia cells, 2) primary and established human acute myeloblastic leukemia cells, and 3) lymphocytes obtained from healthy individuals. The activity of this nuclear exonuclease (exoN) is elevated approximately 6-fold in 1-beta-d-arabinofuranosylcytosine-resistant leukemia cells as compared with drug-sensitive cells, and it differs between two healthy individuals and among three leukemia patients. exoN is a 46-kDa monomer, requires 50 mm KCl and 1 mm magnesium for optimal activity, and shows a preference for single-stranded over duplex DNA. Its physical and enzymatic properties indicate that exoN is a previously uncharacterized enzyme whose activity may confer resistance to clinical nucleoside analogs in leukemia cells.

Address: Division of Experimental Therapeutics, Ontario Cancer Institute, Princess Margaret Hospital and the Department of Medical Biophysics, University of Toronto, Ontario, Canada. [email protected]

DOI: 10.1074/jbc.M001460200

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MeSH Terms: Antimetabolites, Antineoplastic, Arabinonucleotides, Cell Nucleus, Cells, Cultured, Cytidine Monophosphate, DNA-Directed DNA Polymerase, Drug Resistance, Neoplasm, Exodeoxyribonuclease V, Exodeoxyribonucleases, Exonucleases, Humans, Leukemia, Leukemia, Lymphocytic, Chronic, B-Cell, Leukemia, Myeloid, Acute, Lymphocytes, Magnesium, Neoplasm Proteins, Potassium Chloride, Protein Biosynthesis, Time Factors, Transcription, Genetic, Tumor Cells, Cultured, Up-Regulation, Vidarabine Phosphate