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dc.contributor.authorChang, Dennis C.
dc.contributor.authorReppert, Steven M.
dc.date2022-08-11T08:09:30.000
dc.date.accessioned2022-08-23T16:33:12Z
dc.date.available2022-08-23T16:33:12Z
dc.date.issued2003-04-29
dc.date.submitted2012-05-24
dc.identifier.citationCurr Biol. 2003 Apr 29;13(9):758-62.
dc.identifier.issn0960-9822 (Linking)
dc.identifier.pmid12725734
dc.identifier.urihttp://hdl.handle.net/20.500.14038/38051
dc.description.abstractThe essence of the Drosophila circadian clock involves an autoregulatory feedback loop in which PERIOD (PER) and TIMELESS (TIM) inhibit their own transcription by association with the transcriptional activators dCLOCK (dCLK) and CYCLE (CYC). Because PER, dCLK, and CYC each contain a PAS domain, it has been assumed that these interaction domains are important for negative feedback. However, a critical role for PAS-PAS interactions in Drosophila clock function has not been shown. Nuclear transport of PER is also believed to be an essential regulatory step for negative feedback, but this has not been directly tested, and the relevant nuclear localization sequence (NLS) has not been functionally mapped. We evaluated these critical aspects of PER-mediated transcriptional inhibition in Drosophila Schneider 2 (S2) cells. We mapped the dCLK:CYC inhibition domain (CCID) of PER and discovered that it lies in the C terminus, downstream of the PAS domain. Using deletion mutants and site-directed mutagenesis, we identified a novel NLS in the CCID of PER that is a potent regulator of PER's nuclear transport in S2 cells. We further found that nuclear transport, primarily through this novel NLS, is essential for the inhibitory activity of PER. The data indicate that nuclear PER inhibits dCLK:CYC-mediated transcription through a novel domain that additionally contains a potent NLS.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=12725734&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1016/S0960-9822(03)00286-0
dc.subjectARNTL Transcription Factors
dc.subjectAnimals
dc.subjectBasic Helix-Loop-Helix Transcription Factors
dc.subjectChromosome Mapping
dc.subjectCircadian Rhythm
dc.subjectDrosophila
dc.subjectDrosophila Proteins
dc.subjectGene Deletion
dc.subjectImmunoassay
dc.subjectMutagenesis, Site-Directed
dc.subjectNuclear Localization Signals
dc.subjectNuclear Proteins
dc.subjectPeriod Circadian Proteins
dc.subjectProtein Structure, Tertiary
dc.subjectTrans-Activators
dc.subjectTranscription, Genetic
dc.subjectNeuroscience and Neurobiology
dc.titleA novel C-terminal domain of drosophila PERIOD inhibits dCLOCK:CYCLE-mediated transcription
dc.typeJournal Article
dc.source.journaltitleCurrent biology : CB
dc.source.volume13
dc.source.issue9
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/neurobiology_pp/83
dc.identifier.contextkey2911198
html.description.abstract<p>The essence of the Drosophila circadian clock involves an autoregulatory feedback loop in which PERIOD (PER) and TIMELESS (TIM) inhibit their own transcription by association with the transcriptional activators dCLOCK (dCLK) and CYCLE (CYC). Because PER, dCLK, and CYC each contain a PAS domain, it has been assumed that these interaction domains are important for negative feedback. However, a critical role for PAS-PAS interactions in Drosophila clock function has not been shown. Nuclear transport of PER is also believed to be an essential regulatory step for negative feedback, but this has not been directly tested, and the relevant nuclear localization sequence (NLS) has not been functionally mapped. We evaluated these critical aspects of PER-mediated transcriptional inhibition in Drosophila Schneider 2 (S2) cells. We mapped the dCLK:CYC inhibition domain (CCID) of PER and discovered that it lies in the C terminus, downstream of the PAS domain. Using deletion mutants and site-directed mutagenesis, we identified a novel NLS in the CCID of PER that is a potent regulator of PER's nuclear transport in S2 cells. We further found that nuclear transport, primarily through this novel NLS, is essential for the inhibitory activity of PER. The data indicate that nuclear PER inhibits dCLK:CYC-mediated transcription through a novel domain that additionally contains a potent NLS.</p>
dc.identifier.submissionpathneurobiology_pp/83
dc.contributor.departmentReppert Lab
dc.contributor.departmentNeurobiology
dc.source.pages758-62
dc.contributor.studentDennis C. Chang


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