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J. Biol. Chem., Vol. 279, Issue 12, 10848-10854, March 19, 2004

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Repression of Promoter Activity by CNOT2, a Subunit of the Transcription Regulatory Ccr4-Not Complex^*

Carin G. M. Zwartjes, Sandrine Jayne, Debbie L. C. van den Berg, and H. T. Marc Timmers¶

From the Department of Physiological Chemistry, Stratenum STR 3.229, University Medical Center Utrecht, Universiteitsweg 100, Utrecht 3584 CG, The Netherlands

The evolutionary conserved Ccr4-Not complex controls mRNA metabolism at multiple levels in eukaryotic cells. Genetic analysis of not mutants in yeast identifies a negative role in transcription, which is dependent on core promoter structure. To obtain direct support for this we targeted individual core subunits of the human Ccr4-Not complex to promoters in transient transfections of human cells. In this experimental setup we found that the CNOT2 and CNOT9(hRcd1/hCaf40) subunits act as repressors of reporter gene activity. Interestingly, recruitment of other Ccr4-Not subunits did not affect the reporter gene. The major repression function of CNOT2 is localized in a specialized protein motif, the Not-Box. This conserved motif is present in all CNOT2 orthologs and surprisingly also in CNOT3 orthologs. Repression by the Not-Box was sensitive to treatment with the histone deacetylase inhibitor trichostatin A. In addition, mutation of a canonical TATA-box enhanced repression. Our experiments show for the first time direct regulation of promoter activity by components of the Ccr4-Not complex.

Received for publication, October 27, 2003 , and in revised form, January 2, 2004.

^* 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 Fig. 1.

Supported by a NWO-MW Pionier grant.

Supported by a European Union grant.

^¶ Supported by The Netherlands Organization for Scientific Research (NWO) CW Grants 700-50-034 and MW Pionier Grant 900-98-142 and the European Union Grant RTN2–2001-00026. To whom correspondence should be addressed. E-mail: h.t.m.timmers{at}med.uu.nl./.

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