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Molecular and Cellular Biology, August 2005, p. 6380-6390, Vol. 25, No. 15
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.15.6380-6390.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The 3'->5' Exonuclease of Apn1 Provides an Alternative Pathway To Repair 7,8-Dihydro-8-Oxodeoxyguanosine in Saccharomyces cerevisiae

Alexander A. Ishchenko,1 Xiaoming Yang,2 Dindial Ramotar,2* and Murat Saparbaev1*

Groupe "Réparation de l'ADN," UMR 8126 CNRS, Institut Gustave Roussy, 94805 Villejuif Cedex, France,1 University of Montreal, Guy-Bernier Research Centre, 5415 de l'Assomption, Montreal, Quebec H1T 2M4, Canada2

Received 30 December 2004/ Returned for modification 25 January 2005/ Accepted 1 May 2005

The 8-oxo-7,8-dihydrodeoxyguanosine (8oxoG), a major mutagenic DNA lesion, results either from direct oxidation of guanines or misincorporation of 8oxodGTP by DNA polymerases. At present, little is known about the mechanisms preventing the mutagenic action of 8oxodGTP in Saccharomyces cerevisiae. Herein, we report for the first time the identification of an alternative repair pathway for 8oxoG residues initiated by S. cerevisiae AP endonuclease Apn1, which is endowed with a robust progressive 3'->5' exonuclease activity towards duplex DNA. We show that yeast cell extracts, as well as purified Apn1, excise misincorporated 8oxoG, providing a damage-cleansing function to DNA synthesis. Consistent with these results, deletion of both OGG1 encoding 8oxoG-DNA glycosylase and APN1 causes nearly 46-fold synergistic increase in the spontaneous mutation rate, and this enhanced mutagenesis is primarily due to G · C to T · A transversions. Expression of the bacterial 8oxodGTP triphosphotase MutT in the apn1{Delta} ogg1{Delta} mutant reduces the mutagenesis. Taken together, our results indicate that Apn1 is involved in an S. cerevisiae 8-oxoguanine-DNA glycosylase (Ogg1)-independent repair pathway for 8oxoG residues. Interestingly, the human major AP endonuclease, Ape1, also exhibits similar exonuclease activity towards 8oxoG residues, raising the possibility that this enzyme could participate in the prevention of mutations that would otherwise result from the incorporation of 8oxodGTP.

* Corresponding author. Mailing address for Murat Saparbaev: Institut Gustave Roussy, 94805 Villejuif Cedex, France. Phone: 33142115404. Fax: 33142115494. E-mail: smurat{at}igr.fr. Mailing address for Dindial Ramotar: Maisonneuve-Rosemont Hospital, Guy-Bernier Research Center, 5415 Boul. de l'Assomption, Montreal, Quebec, Canada H1T 2M4. Phone: (514) 252-3400, ext. 4684. Fax: (514) 252-3430. E-mail: dramotar.hmr{at}ssss.gouv.qc.ca.

Molecular and Cellular Biology, August 2005, p. 6380-6390, Vol. 25, No. 15
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.15.6380-6390.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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