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J. Biol. Chem., Vol. 279, Issue 11, 10796-10807, March 12, 2004

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S Phase-specific Transcription of the Mouse Ribonucleotide Reductase R2 Gene Requires Both a Proximal Repressive E2F-binding Site and an Upstream Promoter Activating Region^*

Anna Lena Chabes, Stefan Björklund, and Lars Thelander

From the Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87 Umeå, Sweden

Ribonucleotide reductase is essential for supplying a balanced pool of the four deoxyribonucleotides required for DNA synthesis and repair. The active enzyme consists of two non-identical subunits called proteins R1 and R2. There are multiple levels of regulation of ribonucleotide reductase activity, which is highest during the S and G₂ phases of an unperturbed cell cycle in mammalian cells. Previous reports in the literature have indicated that the S phase-specific transcription of the mammalian R2 gene is regulated by a transcriptional block, is dependent on the transcription factor E2F1, or is simply regulated by proteins that bind to promoter CCAAT boxes plus the TATA box. Here, we demonstrate that the S phase-specific transcription of the mouse R2 gene is dependent on an upstream promoter activating region (located at nucleotides (nt) -672 to -527 from the transcription start site) and one proximal promoter repressive element (located at nt -112 to -107) that binds E2F4. Binding to the E2F site is modulated by binding of nuclear factor-Y to an adjacent CCAAT element (nt -79 to -75). The upstream activating region is crucial for overall R2 promoter activity. Mutation of the E2F-binding site leads to premature promoter activation in G₁ and increases overall promoter activity but only when the upstream activating region is present and intact. Therefore, E2F-dependent repression is essential for cell cycle-specific R2 transcription.

Received for publication, November 14, 2003 , and in revised form, December 18, 2003.

^* This work was supported by the Swedish Research Council, the Swedish Foundation for Strategic Research, the Medical Faculty of Umeå University, and the Kempe Foundation. 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.

Present address: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.

To whom correspondence should be addressed. Tel.: 46-90-786-6742; Fax: 46-90-786-9795; E-mail: Lars.Thelander{at}medchem.umu.se.

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