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Molecular and Cellular Biology, August 1999, p. 5316-5325, Vol. 19, No. 8
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

PER and TIM Inhibit the DNA Binding Activity of a Drosophila CLOCK-CYC/dBMAL1 Heterodimer without Disrupting Formation of the Heterodimer: a Basis for Circadian Transcription

Choogon Lee,1 Kiho Bae,1 and Isaac Edery2,*

Graduate Program in Microbiology and Molecular Genetics1 and Department of Molecular Biology and Biochemistry,2 Rutgers University, Center for Advanced Biotechnology and Medicine, Piscataway, New Jersey 08854

Received 9 December 1998/Returned for modification 8 February 1999/Accepted 12 May 1999

The Drosophila CLOCK (dCLOCK) and CYCLE (CYC) (also referred to as dBMAL1) proteins are members of the basic helix-loop-helix PAS (PER-ARNT-SIM) superfamily of transcription factors and are required for high-level expression of the circadian clock genes period (per) and timeless (tim). Several lines of evidence indicate that PER, TIM, or a PER-TIM heterodimer somehow inhibit the transcriptional activity of a putative dCLOCK-CYC complex, generating a negative-feedback loop that is a core element of the Drosophila circadian oscillator. In this report we show that PER and/or TIM inhibits the binding of a dCLOCK-CYC heterodimer to an E-box-containing DNA fragment that is present in the 5' nontranscribed region of per and acts as a circadian enhancer element. Surprisingly, inhibition of this DNA binding activity by PER, TIM, or both is not accompanied by disruption of the association between dCLOCK and CYC. The results suggest that the interaction of PER, TIM, or both with the dCLOCK-CYC heterodimer induces a conformational change or masks protein regions in the heterodimer, leading to a reduction in DNA binding activity. Together with other findings, our results strongly suggest that daily cycles in the association of PER and TIM with the dCLOCK-CYC complex probably contribute to rhythmic expression of per and tim.

* Corresponding author. Mailing address: Department of Molecular Biology and Biochemistry, CABM, 679 Hoes Ln., Piscataway, NJ 08854. Phone: (732) 235-5550. Fax: (732) 235-5318. E-mail: edery{at}mbcl.rutgers.edu.

Molecular and Cellular Biology, August 1999, p. 5316-5325, Vol. 19, No. 8
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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