Regulation of Nuclear Entry of the Drosophila Clock Proteins Period and Timeless

@article{Saez1996RegulationON,
  title={Regulation of Nuclear Entry of the Drosophila Clock Proteins Period and Timeless},
  author={Lino Saez and Michael W. Young},
  journal={Neuron},
  year={1996},
  volume={17},
  pages={911-920}
}
Two genes, period (per) and timeless (tim), are essential for circadian rhythmicity in Drosophila. The encoded proteins (PER and TIM) physically interact. Here, it is shown that TIM and PER accumulate in the cytoplasm when independently expressed in cultured (S2) Drosophila cells. However, the proteins move to the nuclei of these cells if coexpressed. Domains of PER and TIM have been identified that block nuclear localization of the monomeric proteins. In vitro protein interaction studies… 
Post-Translational Regulation and Nuclear Entry of TIMELESS and PERIOD Are Affected in New timeless Mutant
TLDR
An essential role of TIM is established in the timed nuclear entry of PER in Drosophila melanogaster by identifying a novel mutation in the tim gene that eliminates behavioral rhythms while allowing robust expression of TIM and PER.
A Key Temporal Delay in the Circadian Cycle of Drosophila Is Mediated by a Nuclear Localization Signal in the Timeless Protein
TLDR
It is confirmed that TIM is required for the nuclear localization of PER and point to a key role for the TIM NLS in the regulated nuclear accumulation of both proteins.
Drosophila TIM Binds Importin α1, and Acts as an Adapter to Transport PER to the Nucleus
TLDR
It is reported here that nuclear entry of PER-TIM in clock cells, and consequently behavioral rhythms, require a specific member of a classic nuclear import pathway, Importin α1 (IMPα1).
Novel Insights into the Regulation of the Timeless Protein
TLDR
It is proposed that TIM drives cycles of PER expression by regulating its stability, and in turn, PER retains TIM in the nucleus, either for the regulation of its own stability or for a novel nuclear role of TIM.
A TIMELESS-Independent Function for PERIOD Proteins in the Drosophila Clock
TLDR
In the absence of TIM, nuclear PER can function as a potent negative transcriptional regulator and Conversion of PER/TIM heterodimers to nuclear PER proteins appears to be required to complete transcriptional repression and terminate each circadian molecular cycle.
A Role for the PERIOD:PERIOD Homodimer in the Drosophila Circadian Clock
TLDR
This work has confirmed a previous structural model for PER and provided strong evidence that PER homodimers are important for circadian clock function, and found that in addition to PER:TIM complexes, functional PER:PER homodims exist in flies.
Sequential Nuclear Accumulation of the Clock Proteins Period and Timeless in the Pacemaker Neurons of Drosophila melanogaster
TLDR
Several aspects of PER and TIM expression were not predicted by the current mechanistic model of the circadian clock in Drosophila and are inconsistent with the hypothesis that Per and TIM function as obligate heterodimers.
A PER/TIM/DBT interval timer for Drosophila's circadian clock.
TLDR
It is suggested that a cytoplasmic interval timer regulates nuclear translocation of PER/TIM/Doubletime (DBT) and TIM proteins, which are involved in the generation of circadian behavior in Drosophila.
Nuclear Export of Mammalian PERIOD Proteins*
TLDR
Evidence is presented suggesting that nuclear localization of PER proteins is a dynamic process determined by both nuclear import and previously unrecognized nuclear export pathways, and that nuclear export may be a conserved and important feature of circadian regulators.
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.
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References

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TLDR
The data indicate that regulation of PER nuclear entry is critical for circadian oscillations by providing a necessary temporal delay between PER synthesis and its effect on transcription.
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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.
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.
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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.
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TLDR
The results of an immunoelectron microscopic analysis of wild-type flies and per-beta- galactosidase (beta-gal) fusion gene transgenics using a polyclonal anti-PER antibody or an anti- beta-gal antibody suggest that PER acts in that subcellular compartment to affect circadian rhythms.
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TLDR
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TLDR
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TLDR
The Per–Tim complex is a functional unit of the Drosophila circadian clock, and Tim degradation may be the initial response of the clock to light.
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TLDR
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TLDR
The clock gene timeless (tim) is required for circadian rhythmicity in Drosophila and the cyclic expression of tim appears to dictate the timing of PER protein accumulation and nuclear localization, suggesting that tim promotes circadian rhythms of per and tim transcription by restricting per RNA and PERprotein accumulation to separate times of day.
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