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The DNA Repair Activity of Human Redox/Repair Protein APE/Ref-1 Is Inactivated by Phosphorylation¹

Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana 70808 [A. Y., W. A. D.]; Departments of Pediatrics and Biochemistry and Molecular Biology, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202 [M. R. K.]

The human DNA repair protein apurinic/apyrimidinic endonuclease (APE) is a dual-function protein that has important roles in both the repair of baseless sites that arise in DNA and in regulating the redox state of a number of proteins (Ref-1). Although previous attention has been focused on how the human APE/Ref-1 gene may be regulated at the DNA level, we have instead examined if APE/Ref-1 is phosphorylated, and if so how it may affect DNA repair activity. We demonstrate here that APE/Ref-1 is indeed a substrate for phosphorylation by the serine/threonine casein kinases (CK) I and II and protein kinase C. Notably, although phosphorylation by CKI and protein kinase C had no effect whatsoever on the ability of APE/Ref-1 to act at abasic sites in DNA, phosphorylation by CKII completely abolished DNA repair activity. That phosphorylation was responsible for the loss of abasic repair activity was concluded from experiments showing that inactive APE/Ref-1 could be reversed to an active DNA repair protein with phosphatase treatment. These results may help to explain the mechanism by which APE/Ref-1 switches from one unrelated function to another.

¹ Supported by NIH Grants RR09884 (to M. R. K.) and ES07815 (to W. A. D.).

² To whom requests for reprints should be addressed, at Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808. Phone: (504) 763-0937; Fax: (504) 763-3030; E-mail: deutscwa@mhs.pbrc.edu.

Received 9/18/97. Accepted 10/28/97.

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