The Drosophila Clock Gene double-time Encodes a Protein Closely Related to Human Casein Kinase Iε

@article{Kloss1998TheDC,
  title={The Drosophila Clock Gene double-time Encodes a Protein Closely Related to Human Casein Kinase I$\epsilon$},
  author={Brian Kloss and Jeffrey L. Price and Lino Saez and Justin Blau and Adrian Rothenfluh and Cedric S. Wesley and Michael W. Young},
  journal={Cell},
  year={1998},
  volume={94},
  pages={97-107}
}
The cloning of double-time (dbt) is reported. DOUBLETIME protein (DBT) is most closely related to human casein kinase Iepsilon. dbtS and dbtL mutations, which alter period length of Drosophila circadian rhythms, produce single amino acid changes in conserved regions of the predicted kinase. dbtP mutants, which eliminate rhythms of per and tim expression and constitutively overproduce hypophosphorylated PER proteins, abolish most dbt expression. dbt mRNA appears to be expressed in the same cell… 
double-time Is a Novel Drosophila Clock Gene that Regulates PERIOD Protein Accumulation
TLDR
It is proposed that the normal function of DOUBLETIME protein is to reduce the stability and thus the level of accumulation of monomeric PER proteins, which would promote a delay between per/tim transcription and PER/TIM complex function, which is essential for molecular rhythmicity.
Drosophila doubletime Mutations Which either Shorten or Lengthen the Period of Circadian Rhythms Decrease the Protein Kinase Activity of Casein Kinase I
TLDR
Low enzyme activity is associated with both short-period and long-period phenotypes of DBT in Drosophila melanogaster.
Phosphorylation of PERIOD Is Influenced by Cycling Physical Associations of DOUBLE-TIME, PERIOD, and TIMELESS in the Drosophila Clock
TLDR
The varying associations of PER, DBT and TIM appear to determine the onset and duration of nuclear PER function within the Drosophila clock.
Drosophila DBT Lacking Protein Kinase Activity Produces Long-Period and Arrhythmic Circadian Behavioral and Molecular Rhythms
TLDR
This first analysis of adult flies with a virtual lack of D BT activity demonstrates that DBT's kinase activity is necessary for normal circadian rhythms and that a general reduction of DBT Kinase activity does not produce short periods.
The Double-Time Protein Kinase Regulates the Subcellular Localization of the Drosophila Clock Protein Period
TLDR
In this study, control of PER subcellular localization in Drosophila clock cells in vivo is examined and it is found that PER can translocate to the nucleus in tim01 null mutants but only if DBT kinase activity is inhibited, and nuclear PER is a potent transcriptional repressor in dbt mutants in vivo without TIM.
Balance between DBT/CKIepsilon kinase and protein phosphatase activities regulate phosphorylation and stability of Drosophila CLOCK protein.
  • E. Y. Kim, I. Edery
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 2006
TLDR
It is shown that DBT activity is required for the phase-specific hyperphosphorylation of CLK in vivo, an event that correlates with times of maximal repression in per RNA levels, and support a conserved role for dynamic regulation of reversible phosphorylation in directly modulating the activities of circadian transcription factors.
Activating PER Repressor through a DBT-Directed Phosphorylation Switch
TLDR
This study examines the role of the protein kinase Doubletime (DBT), a Drosophila ortholog of human casein kinase I (CKI)ɛ/δ, and shows that several DBT-directed phosphorylations regulate PER activity in an integrated fashion.
The Drosophila double-timeS Mutation Delays the Nuclear Accumulation of period Protein and Affects the Feedback Regulation of period mRNA
TLDR
Results suggest that dbt can regulate the feedback of per protein on its mRNA by delaying the time at which it is translocated to nuclei and altering the level of nuclear PER during the declining phase of the cycle.
Casein kinase Iε Does Not Rescue double-time Function in Drosophila Despite Evolutionarily Conserved Roles in the Circadian Clock
TLDR
Results indicate that hckIε cannot replace the activity of dbt in flies despite the high degree of similarity in primary sequence and kinase function, and expression of hkIε in flies appears to interfere with dbt activity.
Drosophila and Vertebrate Casein Kinase Iδ Exhibits Evolutionary Conservation of Circadian Function
TLDR
A high degree of evolutionary conservation of fly and vertebrate CKIδ and of the functions affected by their period-shortening mutations is demonstrated.
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References

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double-time Is a Novel Drosophila Clock Gene that Regulates PERIOD Protein Accumulation
TLDR
It is proposed that the normal function of DOUBLETIME protein is to reduce the stability and thus the level of accumulation of monomeric PER proteins, which would promote a delay between per/tim transcription and PER/TIM complex function, which is essential for molecular rhythmicity.
Isolation of timeless by PER Protein Interaction: Defective Interaction Between timeless Protein and Long-Period Mutant PERL
TLDR
The cloning of complementary DNAs derived from the tim gene in a two-hybrid screen for PER-interacting proteins and the demonstration of a physical interaction between the tim protein (TIM) and PER in vitro are reported.
Block in nuclear localization of period protein by a second clock mutation, timeless.
TLDR
The studies described here indicate that the nuclear localization of PER is blocked by timeless (tim), a second chromosome mutation that, like per null mutations, abolishes circadian rhythms.
Circadian Cycling of a PERIOD-β-galactosidase Fusion Protein in Drosophila: Evidence for Cyclical Degradation
TLDR
The authors analyzed circadian features of two period-lacZ (per- lacZ) fusion genes in transgenic strains of Drosophila to discuss the posttranscriptional regulation that is necessary for proper cycling of both PER and TIM as well as for clock function.
Regulation of Nuclear Entry of the Drosophila Clock Proteins Period and Timeless
TLDR
The results indicate a mechanism for controlled nuclear localization in which suppression of cytoplasmic localization is accomplished by direct interaction of PER and TIM, and suggest that a checkpoint in the circadian cycle is established by requiring cytopLasmic assembly of a PER/TIM complex as a condition for nuclear transport of either protein.
Two period Homologs: Circadian Expression and Photic Regulation in the Suprachiasmatic Nuclei
TLDR
Phylogenetic analysis supports the existence of a family of mammalian per genes in mammals and advances the knowledge of candidate clock elements in mammals.
Positional Cloning of the Mouse Circadian Clock Gene
TLDR
CLOCK represents the second example of a PAS domain-containing clock protein (besides Drosophila PERIOD), which suggests that this motif may define an evolutionarily conserved feature of the circadian clock mechanism.
Temporal phosphorylation of the Drosophila period protein.
TLDR
It is suggested that the phosphorylation status of PER is an important determinant in the Drosophila clock's time-keeping mechanism.
Regulation of the Drosophila Protein Timeless Suggests a Mechanism for Resetting the Circadian Clock by Light
TLDR
The cyclic expression of TIM protein in adult heads is shown and it lags behind peak levels of TIM RNA by several hours, suggesting that TIM mediates light-induced resetting of the circadian clock.
Drosophila melanogaster deficient in protein kinase A manifests behavior-specific arrhythmia but normal clock function
TLDR
The results suggest that PKA plays a critical role in the flow of temporal information from circadian pacemaker cells to selective behaviors and the proper functioning of elements downstream of the Drosophila timekeeping mechanism.
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