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Nucleic Acids Research, 1995, Vol. 23, No. 24 5027-5033
© 1995

Articles

Trans-complementation by human apurinic endonuclease (Ape) of hypersensitivity to DNa damage and spontaneous mutator phenotype in apn 1- yeast

David M. willson, III, Richard A.O. Bennett, John C. Marquis, Parswa Ansari and Bruce Demple*

Department of molecular and Cellular Toxicology, Harvard School of Public Health Boston, MA 02115, USA

*To whom correspondence should be addressed

Received August 8, 1995. Accepted November 10, 1995.

Abasic (AP) sites in DNA are potentially lethal and mutagenlc. ‘Class II’ AP endonucleases Initiate the repair of these and other DNA lesions. In yeast, the predominant enzyme of this type is Apn1, and its elimination sensitizes the cells to killing by simple alkylatlng agents or oxidants, and raises the rate of spontaneous mutation. We investigated the ability of the major human class II AP endonuclease, Ape, which is structurally unrelated to Apn1, to replace the yeast enzyme In vivo. Confocal immunomlcroscopy studies indicate that ~25% of the Ape expressed in yeast is present in the nucleus. High-level Ape expression corresponding to ~7000 molecules per nucleus, equal to the normal Apn1 copy number, restored resistance to methyl methanesulfonate to near wild-type levels in Apn1-deficient (apn–) yeast. Ape expression in apn1–, yeast provided little protection against H2O2 challenges, consistent with the weak 3-repair diesterase activity of the human enzyme. Ape expression at ~2000 molecules per nucleus reduced the spontaneous mutation rate of apn1– yeast to that seen for wild-type cells. Because Ape has a powerful AP endonuclease but weak 3'-diesterase activity, these findings indicate that endogenously generated AP sites can drive spontaneous mutagenesis.


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