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J. Biol. Chem., Vol. 278, Issue 11, 9005-9012, March 14, 2003
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From the Base excision repair of oxidized
pyrimidines in human DNA is initiated by the DNA
N-glycosylase/apurinic/apyrimidinic (AP) lyase,
human NTH1 (hNTH1), the homolog of Escherichia coli
endonuclease III (Nth). In contrast to Nth, the DNA
N-glycosylase activity of hNTH1 is 7-fold greater than its
AP lyase activity when the DNA substrate contains a thymine glycol (Tg)
opposite adenine (Tg:A) (Marenstein, D. R., Ocampo, M. T. A., Chan, M. K., Altamirano, A., Basu, A. K.,
Boorstein, R. J., Cunningham, R. P., and Teebor, G. W. (2001) J. Biol. Chem. 276, 21242-21249). When Tg is
opposite guanine (Tg:G), the two activities are of the same specific
activity as the AP lyase activity of hNTH1 against Tg:A (Ocampo,
M. T. A., Chaung, W., Marenstein, D. R., Chan, M. K., Altamirano, A., Basu, A. K., Boorstein, R. J.,
Cunningham, R. P., and Teebor, G. W. (2002) Mol. Cell.
Biol. 22, 6111-6121). We demonstrate here that hNTH1 was
inhibited by the product of its DNA N-glycosylase activity
directed against Tg:G, the AP:G site. In contrast, hNTH1 was not as
inhibited by the AP:A site arising from release of Tg from Tg:A.
Addition of human APE1 (AP endonuclease-1) increased dissociation of hNTH1
from the DNA N-glycosylase-generated AP:A site, resulting
in abrogation of AP lyase activity and an increase in turnover of the
DNA N-glycosylase activity of hNTH1. Addition of APE1 did
not abrogate hNTH1 AP lyase activity against Tg:G. The stimulatory
protein YB-1 (Marenstein et al.), added to APE1, resulted
in an additive increase in both activities of hNTH1 regardless of base
pairing. Tg:A is formed by oxidative attack on thymine opposite
adenine. Tg:G is formed by oxidative attack on 5-methylcytosine
opposite guanine (Zuo, S., Boorstein, R. J., and Teebor, G. W. (1995) Nucleic Acids Res. 23, 3239-3243). It is
possible that the in vitro substrate selectivity of
mammalian NTH1 and the concomitant selective stimulation of activity by APE1 are indicative of selective repair of oxidative damage in different regions of the genome.
Substrate Specificity of Human Endonuclease III (hNTH1)
EFFECT OF HUMAN APE1 ON hNTH1 ACTIVITY*
,,,
Department of Pathology and the Kaplan
Comprehensive Cancer Center, New York University School of Medicine,
New York, New York 10016, the § Department of Chemistry,
University of Connecticut, Storrs, Connecticut 06269, and the
¶ Department of Biological Sciences, The University at
Albany, State University of New York, Albany, New York 12222
*
This work was supported by the Department of Pathology, New
York University School of Medicine, and an award from the New York
University School of Medicine Research Bridging Support Fund (to
G. W. T.) and by NIEHS Grant ES 09127 (to A. K. B.) and NIH Grant
GM 46312 (to R. P. C.) from the National Institutes of Health.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: Dept. of
Pathology, New York University Medical Center, 550 First Ave., New
York, NY 10016. Tel.: 212-263-5473; Fax: 212-263-8211; E-mail:
george.teebor@med.nyu.edu.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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