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J. Biol. Chem., Vol. 279, Issue 17, 16912-16917, April 23, 2004

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Differential Requirement for Proliferating Cell Nuclear Antigen in 5' and 3' Nick-directed Excision in Human Mismatch Repair^*

Shuangli Guo, Steven R. Presnell¶, Fenghua Yuan¶, Yanbin Zhang¶, Liya Gu¶, and Guo-Min Li¶||

From the Departments of Molecular and Cellular Biochemistry and ^¶Pathology and Laboratory Medicine, Markey Cancer Center, University of Kentucky Medical Center, Lexington, Kentucky 40536

Proliferating cell nuclear antigen (PCNA) is involved in mammalian mismatch repair at a step prior to or at mismatch excision, but the molecular mechanism of this process is not fully understood. To examine the role of PCNA in mismatch-provoked and nick-directed excision, orientation-specific mismatch removal of heteroduplexes with a pre-existing nick was monitored in human nuclear extracts supplemented with the PCNA inhibitor protein p21. We show here that, whereas 3' nick-directed mismatch excision was completely inhibited by low concentrations of p21 or a p21 C-terminal fusion protein, 5' nick-directed excision was only partially blocked under the same conditions. No further reduction of the 5' excision was detected when a much higher concentration of p21 C-terminal protein was used. These results suggest the following. (i) There is a differential requirement for PCNA in 3' and 5' nick-directed excision; and (ii) 5' nick-directed excision is conducted by a manner either dependent on or independent of PCNA. Our in vitro reconstitution experiments indeed identified a 5' nick-directed excision pathway that is dependent on PCNA, hMutS, and a partially purified fraction from a HeLa nuclear extract.

Received for publication, December 3, 2003 , and in revised form, January 12, 2004.

^* This work was supported in part by NCI, National Institutes of Health Grants CA85377 and CA72956 (to G. -M. L.). 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.

These authors contributed equally to this work.

^|| Holder of the James-Gardner Chair in Cancer Research and to whom correspondence should be addressed: Dept. of Pathology and Laboratory Medicine, University of Kentucky Medical Center, 800 Rose St., Lexington, KY 40536. Tel.: 859-257-7053; Fax: 859-323-2094; E-mail: gmli{at}uky.edu.

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