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Rev-erb2 mRNA Encodes a Stable Protein with a Potential Role in Circadian Clock Regulation

Molecular Zoology Group (J.R., G.T., I.M., V.L., G.B.), Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Centre National de la Recherche Scientifique, Institut National de la Recherche Agronomique, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, 69364 Lyon, France; Institut Pasteur de Lille (B.S.) and Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 545, Lille F-59019, France; and Université de Lille 2, Faculté des Sciences Pharmaceutiques et Biologiques et Faculté de Médecine, Lille F-59006, France

Address all correspondence and requests for reprints to: ¹Gérard Benoit, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5242, Institut de Génomique Fonctionnelle, Ecole Normale Supérieure de Lyon, 46 Allée d’Italie, 69364 Lyon Cedex 07, France. E-mail: Gerard.Benoit{at}ens-lyon.fr.

Circadian rhythms are observed in nearly all aspects of physiology and behavior. In mammals, such biological rhythms are supported by a complex network of self-sustained transcriptional loops and posttranslational modifications, which regulate timely controlled production and degradation of critical factors on a 24-h basis. Among these factors, the orphan nuclear receptor rev-erb plays an essential role by linking together positive and negative regulatory loops. As an essential part of the circadian core clock mechanism, REV-ERB expression shows a precisely scheduled oscillation reflecting the tight control of its production and degradation. In previous studies, we identified two alternative transcripts encoding two protein variants referred to as REV-ERB1 and -2. Interestingly, recent work identified structural elements present only in REV-ERB1 that controls its turnover and thereby influences circadian oscillations. In the present work, we comparatively analyze the two variants and show that REV-ERB2 exhibits a half-life incompatible with a circadian function, suggesting that this variant exerts different biological functions. However, our comparative study clearly indicates undistinguishable DNA-binding properties and transcriptional repression activity as well as a similar regulation mechanism. The only consistent difference appears to be the relative expression level of the two transcripts, rev-erb1 being one to 100 times more expressed than 2 depending on tissue and circadian time. Taking this finding into consideration, we reassessed REV-ERB2 turnover and were able to show that this variant exhibits a reduced half-life when coexpressed with REV-ERB1. We propose that the relative expression levels of the two REV-ERB variants fine-tune the circadian period length by regulating REV-ERB half-life.

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Nuclear Receptors:   REV-ERBα  |  RORα