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J. Biol. Chem., Vol. 278, Issue 45, 44505-44513, November 7, 2003

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The Human Proliferating Cell Nuclear Antigen Regulates Transcriptional Coactivator p300 Activity and Promotes Transcriptional Repression^*

Rui Hong and Debabrata Chakravarti

From the Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6084

Chromatin structure plays an important role in DNA replication, repair, and transcription. p300 is a transcriptional coactivator with protein acetyltransferase activity, and proliferating cell nuclear antigen (PCNA) plays important roles in DNA replication and repair. It has been shown recently that p300 is necessary for DNA synthesis and repair. However, it is not known whether human PCNA, in a reciprocal manner, can regulate the enzymatic activity and transcriptional regulatory properties of p300. Here we show that human PCNA associates with p300 and potently inhibits the acetyltransferase activity and transcriptional activation properties of p300. Surprisingly, PCNA fails to inhibit p300/CBP-associated factor (PCAF) acetyltransferase function as well as PCAF-dependent transcription. Additionally, PCNA potently represses transcription when targeted to chromatin in vivo. Consistent with these observations, using chromatin immunoprecipitation assays, we demonstrate that PCNA recruitment to promoters causes hypoacetylation of chromatin. Together, our results demonstrate for the first time a novel role for human PCNA in transcriptional repression and in modulating chromatin modification. The reciprocal modulation of p300 and PCNA activities by each other provides an example of integrative regulatory cross-talk among chromatin-based processes such as DNA transcription, repair, and synthesis.

Received for publication, March 26, 2003 , and in revised form, August 11, 2003.

^* This work was supported by National Institutes of Health Grant RO1-DK57079 (to D. C.), NIDDK Grant P30-DK50306 from the National Institutes of Health, the Abramson Cancer Center of the University of Pennsylvania, and in part by a grant from the Pennsylvania Department 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.

To whom correspondence should be addressed: 810 BRBII/III, 421 Curie Blvd., Dept. of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6160. Tel.: 215-573-8470; Fax: 215-573-9004; E-mail: debu{at}pharm.med.upenn.edu.

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