Post-translational regulation and nuclear entry of TIMELESS and PERIOD are affected in new timeless mutant

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
Taichi HaraAmita Sehgal

Abstract

The molecular circadian clock consists of a feedback loop in which canonical clock proteins negatively regulate transcription of their own genes. Timed nuclear entry of these proteins is critical, but regulation of this event is poorly understood. In Drosophila melanogaster, the idea that nuclear entry of PERIOD (PER) is controlled by its partner protein TIMELESS (TIM) has been challenged by several studies. We identify here a novel mutation in the tim gene that eliminates behavioral rhythms while allowing robust expression of TIM and PER. Mutant TIM can bind to and stabilize PER. However, neither protein is expressed cyclically, and phosphorylation of both is reduced. In addition, TIM and PER are localized in the cytoplasm at all times of day, and mutant TIM attenuates transcriptional feedback by PER in cultured cells, suggesting that it holds PER in the cytoplasm. In fact, much of the reduced phosphorylation of PER in the new tim mutant appears to result from the cytoplasmic localization of PER. Interestingly, mutating a threonine near the original mutation produces similar phenotypes, raising the possibility that defective phosphorylation is the basis of TIM dysfunction in the novel tim mutant. We also show that a stable for...Continue Reading

References

May 3, 2003·Current Biology : CB·Dennis C Chang, S M Reppert
Jun 28, 2003·Journal of Biological Rhythms·Lesley J Ashmore, Amita Sehgal
Jun 3, 2005·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Shawn A CyranJustin Blau
Sep 6, 2005·Current Biology : CB·Paul E Hardin
Jun 30, 2007·Science·Federica SandrelliCharalambos P Kyriacou
Sep 4, 2009·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Xiangzhong ZhengAmita Sehgal
Sep 24, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Hyuk Wan KoIsaac Edery

Citations

Jun 7, 2014·Annual Review of Biochemistry·Brian R Crane, Michael W Young
Jul 4, 2012·Trends in Neurosciences·Xiangzhong Zheng, Amita Sehgal
Feb 6, 2013·Journal of Biological Rhythms·Pamela MenegazziRodolfo Costa
Oct 19, 2017·Cold Spring Harbor Perspectives in Biology·Koji L Ode, Hiroki R Ueda
May 14, 2014·Molecular and Cellular Biology·Xiangzhong ZhengAmita Sehgal
Oct 13, 2018·FEBS Letters·Juan DuZhangwu Zhao

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