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J. Biol. Chem., Vol. 282, Issue 43, 31349-31357, October 26, 2007

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Circadian Transcription Depends on Limiting Amounts of the Transcription Co-activator nejire/CBP^*

Hsiu-Cheng Hung¹, Christian Maurer¹, Steve A. Kay, and Frank Weber²

From the Biochemie-Zentrum Heidelberg, Ruprecht-Karls Universität Heidelberg, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany and The Scripps Research Institute, La Jolla, California 92037

The circadian clock orchestrates physiological and behavioral activities, including metabolism, neuronal activity, and cell proliferation in synchrony with the environmental cycle of day and night. Here we show that the Drosophila ortholog of the CBP/p300 family of transcription co-activators, nejire (nej), is an intrinsic component of the circadian clock that performs regulatory functions for circadian controlled transcription. Screening of overexpression mutants revealed that gain of nej function was associated with a loss of behavioral and molecular rhythms. Overexpression of NEJ suppresses the long period phenotype of a mutation in the clock gene period (per). NEJ physically interacts through two binding sites with CLOCK and the CLOCK·CYCLE (CLK·CYC) complex. Induction of CLK·CYC-dependent transcripts upon induction of nej expression from a heat-shock promoter showed that NEJ is limiting. Reduced CLK·CYC-mediated transcription in a nej hypomorphic mutant indicates an essential function of NEJ/CBP for CLK·CYC activity and a regulation of circadian transcription by availability of the co-activator. Competition for recruitment of NEJ/CBP provides a potential mechanism for cross-talk between circadian transcription and other CBP-dependent physiological processes.

Received for publication, March 16, 2007 , and in revised form, July 12, 2007.

^* This work was supported by the National Institutes of Health Grant MH51573 (to S. A. K.) and by an Emmy-Noether Fellowship (WE2608/1-2) of the Deutsche Forschungsgemeinschaft (to F. W.). 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 Figs. S1–S4.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Biochemie-Zentrum Heidelberg, Ruprecht-Karls Universität Heidelberg, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany. Tel.: 49-6221-548573; Fax: 49-6221-544769; E-mail: Frank.Weber{at}bzh.uni-heidelberg.de.

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