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J. Biol. Chem., Vol. 283, Issue 19, 13310-13319, May 9, 2008

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The MutS-Proliferating Cell Nuclear Antigen Interaction in Human DNA Mismatch Repair^*

Ravi R. Iyer, Timothy J. Pohlhaus, Sihong Chen, Gregory L. Hura^¶, Leonid Dzantiev, Lorena S. Beese, and Paul Modrich¹

From the Department of Biochemistry and the Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 27710 and the ^¶Physical Bioscience Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720

We have examined the interaction parameters, conformation, and functional significance of the human MutS^· proliferating cell nuclear antigen (PCNA) complex in mismatch repair. The two proteins associate with a 1:1 stoichiometry and a K_D of 0.7 µM in the absence or presence of heteroduplex DNA. PCNA does not influence the affinity of MutS for a mismatch, and mismatch-bound MutS binds PCNA. Small angle x-ray scattering studies have established the molecular parameters of the complex, which are consistent with an elongated conformation in which the two proteins associate in an end-to-end fashion in a manner that does not involve an extended unstructured tether, as has been proposed for yeast MutS and PCNA ( Shell, S. S., Putnam, C. D., and Kolodner, R. D. (2007) Mol. Cell 26, 565-578[CrossRef][Medline] [Order article via Infotrieve] ). MutS variants lacking the PCNA interaction motif are functional in 3'- or 5'-directed mismatch-provoked excision, but display a partial defect in 5'-directed mismatch repair. This finding is consistent with the modest mutability conferred by inactivation of the MutS PCNA interaction motif and suggests that interaction of the replication clamp with other repair protein(s) accounts for the essential role of PCNA in MutS-dependent mismatch repair.

Received for publication, January 23, 2008 , and in revised form, March 6, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants R01 GM45190 and P01 CA92584. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-4 and additional references.

This article was selected as a Paper of the Week.

¹ Investigator of the Howard Hughes Medical Institute. To whom correspondence should be addressed. Tel.: 919-684-2775; Fax: 919-681-7874; E-mail: modrich{at}biochem.duke.edu.

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