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Molecular and Cellular Biology, September 2002, p. 6111-6121, Vol. 22, No. 17
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.17.6111-6121.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Targeted Deletion of mNth1 Reveals a Novel DNA Repair Enzyme Activity

Maria T. A. Ocampo,1 Wenren Chaung,1 Dina R. Marenstein,1 Michael K. Chan,1 Alvin Altamirano,2 Ashis K. Basu,2 Robert J. Boorstein,1 Richard P. Cunningham,3 and George W. Teebor1*

Department of Pathology and Kaplan Comprehensive Cancer Center, New York University Medical Center, New York, New York 10016,1 Department of Chemistry, University of Connecticut, Storrs, Connecticut 06269,2 Department of Biological Sciences, The University at Albany, State University of New York, New York 122223

Received 28 March 2002/ Returned for modification 29 May 2002/ Accepted 7 June 2002

DNA N-glycosylase/AP (apurinic/apyrimidinic) lyase enzymes of the endonuclease III family (nth in Escherichia coli and Nth1 in mammalian organisms) initiate DNA base excision repair of oxidized ring saturated pyrimidine residues. We generated a null mouse (mNth1-/-) by gene targeting. After almost 2 years, such mice exhibited no overt abnormalities. Tissues of mNth1-/- mice contained an enzymatic activity which cleaved DNA at sites of oxidized thymine residues (thymine glycol [Tg]). The activity was greater when Tg was paired with G than with A. This is in contrast to Nth1, which is more active against Tg:A pairs than Tg:G pairs. We suggest that there is a back-up mammalian repair activity which attacks Tg:G pairs with much greater efficiency than Tg:A pairs. The significance of this activity may relate to repair of oxidized 5-methyl cytosine residues (5meCyt). It was shown previously (S. Zuo, R. J. Boorstein, and G. W. Teebor, Nucleic Acids Res. 23:3239-3243, 1995) that both ionizing radiation and chemical oxidation yielded Tg from 5meCyt residues in DNA. Thus, this previously undescribed, and hence novel, back-up enzyme activity may function to repair oxidized 5meCyt residues in DNA while also being sufficient to compensate for the loss of Nth1 in the mutant mice, thereby explaining the noninformative phenotype.

* Corresponding author. Mailing address: Department of Pathology, New York University Medical Center, 550 First Ave., New York, NY 10016. Phone: (212) 263-5473. Fax: (212) 263-8211. E-mail: george.teebor{at}med.nyu.edu.

Molecular and Cellular Biology, September 2002, p. 6111-6121, Vol. 22, No. 17
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.17.6111-6121.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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