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Drosophila doubletime Mutations Which either Shorten or Lengthen the Period of Circadian Rhythms Decrease the Protein Kinase Activity of Casein Kinase I

Fabian Preuss,^1, Jin-Yuan Fan,^1, Madhavi Kalive,^2, Shu Bao,^2, Eric Schuenemann,^1,|| Edward S. Bjes,¹ and Jeffrey L. Price^1*

School of Biological Sciences, University of Missouri—Kansas City, Kansas City, Missouri 64110,¹ Department of Biology, West Virginia University, Morgantown, West Virginia 26506²

Received 15 August 2003/ Returned for modification 9 October 2003/ Accepted 21 October 2003

In both mammals and fruit flies, casein kinase I has been shown to regulate the circadian phosphorylation of the period protein (PER). This phosphorylation regulates the timing of PER's nuclear accumulation and decline, and it is necessary for the generation of circadian rhythms. In Drosophila melanogaster, mutations affecting a casein kinase I (CKI) ortholog called doubletime (dbt) can produce short or long periods. The effects of both a short-period (dbt^S) and long-period (dbt^L) mutation on DBT expression and biochemistry were analyzed. Immunoblot analysis of DBT in fly heads showed that both the dbt^S and dbt^L mutants express DBT at constant levels throughout the day. Glutathione S-transferase pull-down assays and coimmunoprecipitation of DBT and PER showed that wild-type DBT, DBT^S, and DBT^L proteins can bind to PER equivalently and that these interactions are mediated by the evolutionarily conserved N-terminal part of DBT. However, both the dbt^S and dbt^L mutations reduced the CKI-7-sensitive kinase activity of an orthologous Xenopus laevis CKI expressed in Escherichia coli. Moreover, expression of DBT in Drosophila S2 cells produced a CKI-7-sensitive kinase activity which was reduced by both the dbt^S and dbt^L mutations. Thus, lowered enzyme activity is associated with both short-period and long-period phenotypes.

F.P. and J.-Y.F. contributed equally to this work.

Present address: Sun Health Research Institute, Phoenix, Ariz.

Present address: IMS Health, Blue Bell, PA 19422.

^|| Present address: Stowers Institute for Medical Research, Kansas City, MO 64110.

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