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Nucleic Acids Research, 2001, Vol. 29, No. 3 743-752
© 2001 Oxford University Press

Enhanced activity of adenine-DNA glycosylase (Myh) by apurinic/apyrimidinic endonuclease (Ape1) in mammalian base excision repair of an A/GO mismatch

Hanjing Yang, Wendy M. Clendenin, Donny Wong1, Bruce Demple1, Malgorzata M. Slupska, Ju-Huei Chiang and Jeffrey H. Miller*

Department of Microbiology and Molecular Genetics and the Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA and 1Department of Cancer Cell Biology, Harvard School of Public Health, Boston, MA 02115, USA

Adenine-DNA glycosylase MutY of Escherichia coli catalyzes the cleavage of adenine when mismatched with 7,8-dihydro-8-oxoguanine (GO), an oxidatively damaged base. The biological outcome is the prevention of C/G->A/T transversions. The molecular mechanism of base excision repair (BER) of A/GO in mammals is not well understood. In this study we report stimulation of mammalian adenine-DNA glycosylase activity by apurinic/apyrimidinic (AP) endonuclease using murine homolog of MutY (Myh) and human AP endonuclease (Ape1), which shares 94% amino acid identity with its murine homolog Apex. After removal of adenine by the Myh glycosylase activity, intact AP DNA remains due to lack of an efficient Myh AP lyase activity. The study of wild-type Ape1 and its catalytic mutant H309N demonstrates that Ape1 catalytic activity is required for formation of cleaved AP DNA. It also appears that Ape1 stimulates Myh glycosylase activity by increasing formation of the Myh–DNA complex. This stimulation is independent of the catalytic activity of Ape1. Consequently, Ape1 preserves the Myh preference for A/GO over A/G and improves overall glycosylase efficiency. Our study suggests that protein–protein interactions may occur in vivo to achieve efficient BER of A/GO.

* To whom correspondence should be addressed at: Department of Microbiology and Molecular Genetics, 1602 Molecular Sciences Building, 405 Hilgard Avenue, Los Angeles, CA 90095, USA. Tel: +1 310 825 8460; Fax: +1 310 206 3088; Email: jhmiller{at}mbi.ucla.edu


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