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J. Biol. Chem., Vol. 281, Issue 25, 17528-17539, June 23, 2006

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Mechanism of Proliferating Cell Nuclear Antigen Clamp Opening by Replication Factor C^*

Nina Y. Yao, Aaron Johnson, Greg D. Bowman¹, John Kuriyan^¶||, and Mike O'Donnell^¶2

From the Rockefeller University and the ^¶Howard Hughes Medical Institute, New York, New York 10021 and the ^||Departments of Molecular and Cell Biology and Chemistry, Howard Hughes Medical Institute, University of California, and the Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720

The eukaryotic replication factor C (RFC) clamp loader is an AAA+ spiral-shaped heteropentamer that opens and closes the circular proliferating cell nuclear antigen (PCNA) clamp processivity factor on DNA. In this study, we examined the roles of individual RFC subunits in opening the PCNA clamp. Interestingly, Rfc1, which occupies the position analogous to the clamp-opening subunit in the Escherichia coli clamp loader, is not required to open PCNA. The Rfc5 subunit is required to open PCNA. Consistent with this result, Rfc2·3·4·5 and Rfc2·5 subassemblies are capable of opening and unloading PCNA from circular DNA. Rfc5 is positioned opposite the PCNA interface from Rfc1, and therefore, its action with Rfc2 in opening PCNA indicates that PCNA is opened from the opposite side of the interface that the E. coli wrench acts upon. This marks a significant departure in the mechanism of eukaryotic and prokaryotic clamp loaders. Interestingly, the Rad·RFC DNA damage checkpoint clamp loader unloads PCNA clamps from DNA. We propose that Rad·RFC may clear PCNA from DNA to facilitate shutdown of replication in the face of DNA damage.

Received for publication, February 9, 2006 , and in revised form, April 5, 2006.

^* This work was supported by National Institutes of Health Grants GM38839 (to M. O. D.) and GM45547 (to J. K.) and by a Ruth L. Kirschstein National Research Service award from NIGMS, National Institutes of Health (to G. D. B.). 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 Present address: Dept. of Biophysics, The Johns Hopkins University, Baltimore, MD 21218.

² To whom correspondence should be addressed: Lab. of DNA Replication, Howard Hughes Medical Inst., The Rockefeller University, 1230 York Ave., New York, NY 10021. Tel.: 212-327-7255; Fax: 212-327-7253; E-mail: odonnel{at}mail.rockefeller.edu.

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