A DOUBLETIME Kinase Binding Domain on the <i>Drosophila</i> PERIOD Protein Is Essential for Its Hyperphosphorylation, Transcriptional Repression, and Circadian Clock Function

Kim, Eun Young; Ko, Hyuk Wan; Yu, Wangjie; Hardin, Paul E.; Edery, Isaac

doi:10.1128/mcb.02339-06

Cited by 105 publications

(153 citation statements)

References 77 publications

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“…Because DBT controls the timing of PER's nuclear accumulation so that it does not occur until after the per/tim mRNA levels have peaked, molecular rhythms of per and tim mRNA are possible . Additional regulation has been proposed to occur at the level of PER's capacity to negatively regulate its transcription factor target (CLK/CYC) (Nawathean and Rosbash 2004;Kim and Edery 2006;Yu et al 2006;Kim et al 2007;Nawathean et al 2007).…”

Section: Discussionmentioning

confidence: 99%

“…It was first shown that PER was rhythmically phosphorylated (Edery et al 1994), and isolation and analysis of the dbt mutants in Drosophila then showed that casein kinase I (CKI) targets PER for phosphorylation and degradation Price et al 1998;Rothenfluh et al 2000a;Suri et al 2000;Muskus et al 2007). Doubletime (DBT) has also been proposed to regulate the nuclear localization (Bao et al 2001;Cyran et al 2005;Nawathean et al 2007) and the repressor capacity of PER (Nawathean and Rosbash 2004;Kim et al 2007;Nawathean et al 2007), as well as the phosphorylation of CLK protein (Kim and Edery 2006;Yu et al 2006). In addition, two other kinases [casein kinase II, CKII (Lin et al 2002) and SGG (Martinek et al 2001)] and two protein phosphatases [PP2A (Sathyanarayanan et al 2004;Fang et al 2007) and PP1 (Fang et al 2007)] contribute to rhythmic phosphorylation of clock proteins.…”

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confidence: 99%

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Drosophila and Vertebrate Casein Kinase Iδ Exhibits Evolutionary Conservation of Circadian Function

Fan

Preuss²,

Muskus

et al. 2009

Genetics

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Mutations lowering the kinase activity of Drosophila Doubletime (DBT) and vertebrate casein kinase Ie/d (CKIe/d) produce long-period, short-period, and arrhythmic circadian rhythms. Since most ckI shortperiod mutants have been isolated in mammals, while the long-period mutants have been found mostly in Drosophila, lowered kinase activity may have opposite consequences in flies and vertebrates, because of differences between the kinases or their circadian mechanisms. However, the results of this article establish that the Drosophila dbt mutations have similar effects on period (PER) protein phosphorylation by the fly and vertebrate enzymes in vitro and that Drosophila DBT has an inhibitory C-terminal domain and exhibits autophosphorylation, as does vertebrate CKIe/d. Moreover, expression of either Drosophila DBT or the vertebrate CKId kinase carrying the Drosophila dbt S or vertebrate tau mutations in all circadian cells leads to short-period circadian rhythms. By contrast, vertebrate CKId carrying the dbt L mutation does not lengthen circadian rhythms, while Drosophila DBT L does. Different effects of the dbt S and tau mutations on the oscillations of PER phosphorylation suggest that the mutations shorten the circadian period differently. The results demonstrate a high degree of evolutionary conservation of fly and vertebrate CKId and of the functions affected by their period-shortening mutations.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Drosophila and Vertebrate Casein Kinase Iδ Exhibits Evolutionary Conservation of Circadian Function

Fan

Preuss²,

Muskus

et al. 2009

Genetics

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“…During this time, PER and TIM progressively associate in distinct foci, which are lost as PER and TIM dissociate and move to the nucleus. In the nucleus, PER, DBT, and possibly TIM, associate with Clock/Cycle complexes, inhibiting transcription of Clock/cycle-dependent genes including per and tim (see also Kim et al 2007;Nawathean et al 2007). The duration of the PER/TIM complex in the cytoplasm is affected by PER L which delays the onset of nuclear accumulation by about 3 hours.…”

Section: Discussionmentioning

confidence: 99%

A PER/TIM/DBT Interval Timer forDrosophila's Circadian Clock

Sáez¹,

Meyer²,

Young³

2007

Cold Spring Harbor Symposia on Quantitative Biology

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Circadian rhythms in Drosophila are supported by a negative feedback loop, in which PERIOD (PER) and Timeless (TIM) shut down their own transcription as they translocate once a day from the cytoplasm of clock-containing cells to the nucleus. Period length is partially determined by an interval of cytoplasmic retention of the TIM and PER proteins. To study this process, we examined PER/TIM/Doubletime (DBT) physical interactions and nuclear translocation by imaging individual cultured Drosophila cells. Using live cell video microscopy and green fluorescent protein (GFP) tags, we observed dynamic patterns of stability and localization for DBT, PER, and TIM that resembled those previously found in vivo. These studies suggest that a cytoplasmic interval timer regulates nuclear translocation of these proteins. The cultured cell assay provides a potent system to study interactions among new and known genes involved in the generation of circadian behavior.

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“…For example, Drosophila PER has been proposed to inhibit circadian transcription by recruiting kinases to the CLK/CYC complex Kim et al 2007). Consistent with this view, a recent failure to detect an association of wildtype PER with DNA by chromatin immunoprecipitation (ChIP) was interpreted to suggest that PER normally promotes phosphorylation by interacting only transiently with chromatin-bound CLK (Yu et al 2009).…”

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confidence: 96%

Dynamic PER repression mechanisms in the Drosophila circadian clock: from on-DNA to off-DNA

Menet¹,

Abruzzi²,

Desrochers³

et al. 2010

Genes Dev.

131

161

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Transcriptional feedback loops are central to the generation and maintenance of circadian rhythms. In animal systems as well as Neurospora, transcriptional repression is believed to occur by catalytic post-translational events. We report here in the Drosophila model two different mechanisms by which the circadian repressor PERIOD (PER) inhibits CLOCK/CYCLE (CLK/CYC)-mediated transcription. First, PER is recruited to circadian promoters, which leads to the nighttime decrease of CLK/CYC activity. This decrease is proportional to PER levels on DNA, and PER recruitment probably occurs via CLK. Then CLK is released from DNA and sequestered in a strong,~1:1 PER-CLK off-DNA complex. The data indicate that the PER levels bound to CLK change dynamically and are important for repression, first on-DNA and then off-DNA. They also suggest that these mechanisms occur upstream of post-translational events, and that elements of this two-step mechanism likely apply to mammals.[keywords: Chromatin immunoprecipitation; circadian; negative feedback loop; tiling array; transcriptional oscillations] Supplemental material is available at http://www.genesdev.org.

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A DOUBLETIME Kinase Binding Domain on the Drosophila PERIOD Protein Is Essential for Its Hyperphosphorylation, Transcriptional Repression, and Circadian Clock Function

Cited by 105 publications

References 77 publications

Drosophila and Vertebrate Casein Kinase Iδ Exhibits Evolutionary Conservation of Circadian Function

Drosophila and Vertebrate Casein Kinase Iδ Exhibits Evolutionary Conservation of Circadian Function

A PER/TIM/DBT Interval Timer forDrosophila's Circadian Clock

Dynamic PER repression mechanisms in the Drosophila circadian clock: from on-DNA to off-DNA

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