Journal of Biological Chemistry
Volume 276, Issue 52, 28 December 2001, Pages 48781-48789
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DNA: REPLICATION REPAIR AND RECOMBINATION
Regulatory Roles of p21 and Apurinic/Apyrimidinic Endonuclease 1 in Base Excision Repair*

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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 δ. 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 β, 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 β, DNA polymerase δ, 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.

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Published, JBC Papers in Press, October 18, 2001, DOI 10.1074/jbc.M109626200

*

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).