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Molecular and Cellular Biology, July 2007, p. 5002-5013, Vol. 27, No. 13
0270-7306/07/$08.00+0     doi:10.1128/MCB.02338-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

A Small Conserved Domain of Drosophila PERIOD Is Important for Circadian Phosphorylation, Nuclear Localization, and Transcriptional Repressor Activity{triangledown}

Pipat Nawathean, Dan Stoleru, and Michael Rosbash*

Howard Hughes Medical Institute and Department of Biology, Brandeis University, Waltham, Massachusetts 02454

Received 15 December 2006/ Returned for modification 2 February 2007/ Accepted 11 April 2007

We identify in this study a 27-amino-acid motif which is conserved between the Drosophila melanogaster period protein (PER) and the three mammalian PERs. Characterization of PER lacking this motif (PER{Delta}) shows that it is important for phosphorylation of Drosophila PER by casein kinase I{varepsilon} (CKI{varepsilon}; doubletime protein or DBT) and CKII. S2 cell assays indicate that the domain also contributes significantly to PER nuclear localization as well as to PER transcriptional repressor activity. These two phenomena appear linked, since PER{Delta} transcriptional repressor activity in S2 cells was restored when nuclear localization was facilitated. Two less direct assays of PER{Delta} activity in flies can be interpreted similarly. The separate assay of nuclear import and export suggests that the domain functions in part to facilitate PER phosphorylation within the cytoplasm, which in turn promotes nuclear entry. As there is evidence that the kinases also function within the nucleus to promote transcriptional repression, we suggest that there is a subsequent collaboration between phosphorylated PER and the kinases to repress CLK-CYC activity, probably through the phosphorylation of CLK. This is then followed by additional PER phosphorylation, which occurs within the nucleus and leads to PER degradation.

* Corresponding author. Mailing address: Howard Hughes Medical Institute and Department of Biology, Brandeis University, Waltham, MA 02454. Phone: (781) 736-3161. Fax: (781) 736-3164. E-mail: rosbash{at}brandeis.edu

{triangledown} Published ahead of print on 23 April 2007.

Molecular and Cellular Biology, July 2007, p. 5002-5013, Vol. 27, No. 13
0270-7306/07/$08.00+0     doi:10.1128/MCB.02338-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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