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Originally published In Press as doi:10.1074/jbc.M203384200 on May 31, 2002

J. Biol. Chem., Vol. 277, Issue 32, 28663-28668, August 9, 2002
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Influences of Base Excision Repair Defects on the Lethality and Mutagenicity Induced by Me-lex, a Sequence-selective N3-Adenine Methylating Agent*

Paola Montiab, Paola Campomenosiab, Yari Ciribillia, Raffaella Iannonea, Alberto Ingaa, Dharini Shahef, Gina Scottg, Philip A. Burnsg, Paola Menichinia, Angelo Abbondandoloai, Barry Goldefj, and Gilberto Fronzaak

From the a Mutagenesis Laboratory, National Cancer Research Institute (IST), L.go R. Benzi, 10, 16132-Genova, Italy, the e Eppley Institute for Research in Cancer and f Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska 69198-6805, g School of Medicine, University of Leeds, LS2 9JT Leeds, United Kingdom, and the i Department of Oncology, Biology and Genetics, University of Genova, 16132-Genova, Italy

Due to its minor groove selectivity, Me-lex preferentially generates N3-methyladenine (3-MeA) adducts in double-stranded DNA. We undertook a genetic approach in yeast to establish the influence of base excision repair (BER) defects on the processing of Me-lex lesions on plasmid DNA that harbors the p53 cDNA as target. We constructed a panel of isogenic strains containing a reporter gene to test p53 function and the following gene deletions: Delta mag1, Delta apn1apn2, and Delta apn1apn2mag1. When compared with the wild-type strain, a decrease in survival was observed in Delta mag1, Delta apn1apn2, and Delta apn1apn2mag1. The Me-lex-induced mutation frequency increased in the following order: wild type < Delta mag1< Delta apn1apn2 = Delta apn1apn2mag1. A total of 77 mutants (23 in wild type, 31 in Delta mag1, and 23 in Delta apn1apn2) were sequenced. Eighty-one independent mutations (24 in wild type, 34 in Delta mag1, and 23 in Delta apn1apn2) were detected. The majority of base pair substitutions were AT-targeted in all strains (14/23, 61% in wild type; 20/34, 59%, in Delta mag1; and 14/23, 61%, in Delta apn1apn2). The Mag1 deletion was associated with a significant decrease of GC > AT transitions when compared with both the wild-type and the AP endonuclease mutants. This is the first time that the impact of Mag1 and/or AP endonuclease defects on the mutational spectra caused by 3-MeA has been determined. The results suggest that 3-MeA is critical for Me-lex cytotoxicity and that its mutagenicity is slightly elevated in the absence of Mag1 glycosylase activity but significantly higher in the absence of AP endonuclease activity.

* This work was supported by Grant RO1 CA 29088 from the National Institutes of Health (to B. G.), by the University of Nebraska Medical Center Graduate Fellowship (to D. S.), and partially by the Associazione Italiana per la Ricerca sul Cancro (AIRC) and by European Community contract number 17225-2000-12 F1ED ISP IT.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.

This work is dedicated to Giovanni Battista Fronza with love.

b These two authors contributed equally to this work.

j To whom correspondence may be addressed. E-mail: bgold@unmc.edu.

k To whom correspondence may be addressed. E-mail: gilberto.fronza@istge.it.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.


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