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J. Biol. Chem., Vol. 275, Issue 40, 31009-31015, October 6, 2000
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From the Department of Pharmacology, Yale University School of
Medicine, New Haven, Connecticut 06520
A Novel Action of Human Apurinic/Apyrimidinic
Endonuclease
EXCISION OF L-CONFIGURATION DEOXYRIBONUCLEOSIDE
ANALOGS FROM THE 3' TERMINI OF DNA*
-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 > -L-2',3'-dideoxy-2',3'-didehydro-5-fluorocytidine > -L-2',3'-dideoxycytidine > -L-2',3'-dideoxy-3'-thiocytidine > -D-2',3'-dideoxycytidine > -D-2',2'-difluorodeoxycytidine > -D-2'-deoxycytidine 
-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.
*
This work was supported by NCI, National Institutes of
Health, Grants CA 63477 and AI 39204.The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Department of
Pharmacology, Yale University School of Medicine, Sterling Hall of
Medicine, B315, 333 Cedar St., New Haven, CT 06520. Tel.: 203-785-7118; Fax: 203-785-7129; E-mail: Cheng.lab@yale.edu.
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