A novel action of human apurinic/apyrimidinic endonuclease. Excision of L-configuration deoxyribonucleoside analogs from the 3' termini of DNA

Kai Ming Chou, Marina Kukhanova, Yung Chi Cheng

Research output: Contribution to journalArticle

102 Citations (Scopus)

Abstract

β-L-Dioxolane-cytidine (L-OddC, BCH-4556, Troxacitabine) is a novel unnatural stereochemical nucleoside analog that is under phase II clinical study for cancer treatment. This nucleoside analog could be phosphorylated and subsequently incorporated into the 3' terminus of DNA. The cytotoxicity of L-OddC was correlated with the amount of L-OddCMP in DNA, which depends on the incorporation by DNA polymerases and the removal by exonucleases. Here we reported the purification and identification of the major enzyme that could preferentially remove L-OddCMP compared with dCMP from the 3' termini of DNA in human cells. Surprisingly, this enzyme was found to be apurinic/apyrimidinic endonuclease (APE1) (1), a well characterized DNA base excision repair protein. APE1 preferred to remove L- over D-configuration nucleosides from 3' termini of DNA. The efficiency of removal of these deoxycytidine analogs were as follows: L-OddC > β-L-2',3'-dideoxy-2',3'-didehydro-5-fluorocytidine > β-L-2',3'-dideoxycytidine > β-L-2',3'-dideoxy-3'-thiocytidine > β-D-2',3'-dideoxycytidine > β-D-2',2'-difluorodeoxycytidine > β-D-2'-deoxycytidine β-D-arabinofuranosylcytosine. This report is the first demonstration that an exonuclease can preferentially excise L-configuration nucleoside analogs. This discovery suggests that APE1 could be critical for the activity of L-OddC or other L-nucleoside analogs and may play additional important roles in cells that were not previously known.

Original languageEnglish (US)
Pages (from-to)31009-31015
Number of pages7
JournalJournal of Biological Chemistry
Volume275
Issue number40
StatePublished - Oct 6 2000
Externally publishedYes

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DNA-(Apurinic or Apyrimidinic Site) Lyase
Deoxyribonucleosides
Endonucleases
Nucleosides
Zalcitabine
DNA
Exonucleases
Deoxycytidine
gemcitabine
Cytidine
Oncology
Cytarabine
DNA-Directed DNA Polymerase
Enzymes
Cytotoxicity
DNA Repair
Purification
Repair
Demonstrations
Cells

ASJC Scopus subject areas

  • Biochemistry

Cite this

A novel action of human apurinic/apyrimidinic endonuclease. Excision of L-configuration deoxyribonucleoside analogs from the 3' termini of DNA. / Chou, Kai Ming; Kukhanova, Marina; Cheng, Yung Chi.

In: Journal of Biological Chemistry, Vol. 275, No. 40, 06.10.2000, p. 31009-31015.

Research output: Contribution to journalArticle

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abstract = "β-L-Dioxolane-cytidine (L-OddC, BCH-4556, Troxacitabine) is a novel unnatural stereochemical nucleoside analog that is under phase II clinical study for cancer treatment. This nucleoside analog could be phosphorylated and subsequently incorporated into the 3' terminus of DNA. The cytotoxicity of L-OddC was correlated with the amount of L-OddCMP in DNA, which depends on the incorporation by DNA polymerases and the removal by exonucleases. Here we reported the purification and identification of the major enzyme that could preferentially remove L-OddCMP compared with dCMP from the 3' termini of DNA in human cells. Surprisingly, this enzyme was found to be apurinic/apyrimidinic endonuclease (APE1) (1), a well characterized DNA base excision repair protein. APE1 preferred to remove L- over D-configuration nucleosides from 3' termini of DNA. The efficiency of removal of these deoxycytidine analogs were as follows: L-OddC > β-L-2',3'-dideoxy-2',3'-didehydro-5-fluorocytidine > β-L-2',3'-dideoxycytidine > β-L-2',3'-dideoxy-3'-thiocytidine > β-D-2',3'-dideoxycytidine > β-D-2',2'-difluorodeoxycytidine > β-D-2'-deoxycytidine β-D-arabinofuranosylcytosine. This report is the first demonstration that an exonuclease can preferentially excise L-configuration nucleoside analogs. This discovery suggests that APE1 could be critical for the activity of L-OddC or other L-nucleoside analogs and may play additional important roles in cells that were not previously known.",
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