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Originally published In Press as doi:10.1074/jbc.M109626200 on October 18, 2001

J. Biol. Chem., Vol. 276, Issue 52, 48781-48789, December 28, 2001
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Regulatory Roles of p21 and Apurinic/Apyrimidinic Endonuclease 1 in Base Excision Repair*

Samson TomDagger , Tamara A. RanalliDagger , Vladimir N. Podust§, and Robert A. BambaraDagger ||

From the Dagger  Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642 and the § Department of Molecular Biology, Vanderbilt University, Nashville, Tennessee 37232

Many types of DNA damage induce a cellular response that inhibits replication but allows repair by up-regulating the p53 pathway and inducing p21Cip1, Waf1, Sdi1. The p21 regulatory protein can bind proliferating cell nuclear antigen (PCNA) and prohibit DNA replication. We show here that p21 also inhibits PCNA stimulation of long patch base excision repair (BER) in vitro. p21 disrupts PCNA-directed stimulation of flap endonuclease 1 (FEN1), DNA ligase I, and DNA polymerase delta . The dilemma is to understand how p21 prevents DNA replication but allows BER in vivo. Differential regulation by p21 is likely to relate to the utilization of DNA polymerase beta , which is not sensitive to p21, in the repair pathway. We have also found that apurinic/apyrimidinic endonuclease 1 (APE1) stimulates long patch BER. Furthermore, neither APE1 activity nor its ability to stimulate long patch BER is significantly affected by p21 in vitro. We propose that APE1 serves as an assembly and coordination factor for long patch BER proteins. APE1 initially cleaves the DNA and then facilitates the sequential binding and catalysis by DNA polymerase beta , DNA polymerase delta , FEN1, and DNA ligase I. This model implies that BER can be regulated differentially, based upon the assembly of relevant proteins around APE1 in the presence or absence of PCNA.

* This research was supported in part by National Institutes of Health Grant GM24441 and by an E. H. Hooker Fellowship (to S. T.).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.

Supported by National Institutes of Health Grant GM52948 (to Ellen Fanning).

|| To whom correspondence should be addressed: Dept. of Biochemistry and Biophysics, University of Rochester Medical Center, 601 Elmwood Ave., Box 712, Rochester, NY 14642. Tel.: 716-275-3269; Fax: 716-271-2683; E-mail: robert_bambara@urmc.rochester.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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Copyright © 2001 by the American Society for Biochemistry and Molecular Biology.