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J. Biol. Chem., Vol. 280, Issue 48, 39752-39761, December 2, 2005

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Human Mismatch Repair

RECONSTITUTION OF A NICK-DIRECTED BIDIRECTIONAL REACTION^*

Nicoleta Constantin1, Leonid Dzantiev1, Farid A. Kadyrov, and Paul Modrich2

From the Department of Biochemistry and Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 27710

Bidirectional mismatch repair directed by a strand break located 3' or 5' to the mispair has been reconstituted using seven purified human activities: MutS, MutL, EXOI, replication protein A (RPA), proliferating cell nuclear antigen (PCNA), replication factor C (RFC) and DNA polymerase . In addition to DNA polymerase , PCNA, RFC, and RPA, 5'-directed repair depends on MutS and EXOI, whereas 3'-directed mismatch correction also requires MutL. The repair reaction displays specificity for DNA polymerase , an effect that presumably reflects interactions with other repair activities. Because previous studies have suggested potential involvement of the editing function of a replicative polymerase in mismatch-provoked excision, we have evaluated possible participation of DNA polymerase in the excision step of repair. RFC and PCNA dramatically activate polymerase -mediated hydrolysis of a primer-template. Nevertheless, the contribution of the polymerase to mismatch-provoked excision is very limited, both in the purified system and in HeLa extracts, as judged by in vitro assay using nicked circular heteroplex DNAs. Thus, excision and repair in the purified system containing polymerase are reduced 10-fold upon omission of EXOI or by substitution of a catalytically dead form of the exonuclease. Furthermore, aphidicolin inhibits both 3'- and 5'-directed excision in HeLa nuclear extracts by only 20–30%. Although this modest inhibition could be because of nonspecific effects, it may indicate limited dependence of bidirectional excision on an aphidicolin-sensitive DNA polymerase.

Received for publication, September 2, 2005 , and in revised form, September 26, 2005.

^* This work was supported in part by Grant GM45190 from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² Investigator of the Howard Hughes Medical Institute. To whom correspondence should be addressed: Howard Hughes Medical Institute and Dept. of Biochemistry, Box 3711, Durham, NC 27710. Tel.: 919-684-2775; Fax: 919-681-7874; E-mail: modrich{at}biochem.duke.edu.

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